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Signal Transduction

Research on signal transduction events in the cause and maintenance of cancers.

Labs in This Area

 Sarki Abdulkadir Lab

Studying the mechanisms of prostate cancer initiation, progression and recurrence and strategies to therapeutically target these processes

Research Description

Our laboratory focuses on understanding the molecular mechanisms that drive prostate cancer initiation, progression and recurrence with the ultimate goal of developing therapeutic strategies that target these processes. Our approach includes the genomic analysis of human tumors, cell culture studies and the use of genetically engineered mouse models. We have a strong interest in genomics and gene regulation, oncogenic kinases as potential molecular therapeutic targets and the use of in vivo lineage tracing to define the fates of specific cell populations in tumorigenesis.

Specific projects include:

The role of the oncogenic serine/threonine kinase PIM1 in prostate cancer - PIM1 is coexpressed with c-MYC and dramatically enhances c-MYC-driven prostate tumorigenesis in a kinase-dependent manner. Notably, PIM1 is induced in tumors by hypoxia, radiation and treatment with docetaxel, a common but largely ineffective option for patients with advanced castration-resistant prostate cancer. PIM1 induction by hypoxia/radiation/docetaxel promotes prostate cancer cell survival and therapeutic resistance. Therefore, PIM1 may represent a valuable therapeutic target in prostate cancer. We are using new mouse models of prostate cancer for testing the efficacy of novel PIM1 kinase inhibitors in treating prostate cancer and reversing therapeutic resistance. We have also identified novel candidate PIM1-interacting proteins in prostate epithelial cells. Among the proteins identified are a MYC transcriptional cofactor and a prostate stem cell marker/regulator. We are investigating how PIM1 promotes prostate tumorigenesis by phosphorylating these substrates involved in regulating MYC transcriptional activity and stem cell function.

Cellular and molecular determinants of prostate cancer recurrence - A major clinical problem in prostate cancer is that of tumor recurrence following initial apparently successful therapy. Recurrent tumors may arise from a small number of "cancer stem-like cells" that survive the initial therapeutic intervention and have the capacity to regenerate the tumor. We are using lineage tracing to examine the competence of specific prostate epithelial cell types to regenerate tumors following therapy in mice.

Targeting lethal prostate cancer – We are using our mouse model of lethal prostate cancer based on alterations in Myc, Pten and Tp53 to develop new targeted therapies. One current project involves the targeting of EphB4 receptor tyrosine kinase using an antagonist as a therapeutic strategy.

For more information, see Dr. Abdulkadir's faculty profile.

Publications

Rodríguez Y, Unno K, Truica MI, Chalmers ZR, Yoo YA, Vatapalli R, Sagar V, Yu J, Lysy B, Hussain M, Han H, Abdulkadir SA. A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2022 Jun 6;82(11):2110-2123.

Chalmers ZR, Burns MC, Ebot EM, Frampton GM, Ross JS, Hussain MHA, Abdulkadir SA. Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2-ERG fusions. Prostate Cancer Prostatic Dis. 2021 Jun;24(2):558-566.

Unno K, Chalmers ZR, Pamarthy S, Vatapalli R, Rodriguez Y, Lysy B, Mok H, Sagar V, Han H, Yoo YA, Ku SY, Beltran H, Zhao Y, Abdulkadir SA. Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer. Cancer Res. 2021 Apr 15;81(8):2157-2170.

Sagar V, Vatapalli R, Lysy B, Pamarthy S, Anker JF, Rodriguez Y, Han H, Unno K, Stadler WM, Catalona WJ, Hussain M, Gill PS, Abdulkadir SA. EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells. Cell Death and Disease. November 2019.

Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I, Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell.  November 2019.

Njoroge RN, Vatapalli RJ, Abdulkadir SA. Organoids increase the predictive value of in vitro cancer chemoprevention studies for in vivo outcome. Frontiers in Oncology. January 2019.

See Dr. Abdulkadir's publications in PubMed.

Contact Us

Dr. Abdulkadir
Lab Telephone: 312-503-5031

 Daniel Arango Lab

Investigating the role of post-transcriptional modifications of RNA in the proliferation, differentiation, and survival of cancer cells

Research Description

Translation is the mechanism by which proteins are made from the information stored in the genetic code. This process is achieved with the help of RNA molecules such as ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA (mRNA). While translation is a tightly regulated process, global perturbations in protein synthesis are observed in stress conditions, cancer, and aging, highlighting the regulatory mechanisms of translation as potential targets in cancer and age-related disorders. One poorly characterized layer of translation regulation is the epitranscriptome, defined as the set of more than 140 ribonucleotide modifications that alter the biochemical properties and function of all classes of RNA, including rRNA, tRNA, and mRNA. While the distribution and function for most ribonucleotide modifications are undefined, the enzymes responsible for depositing RNA modifications are dynamic and sensitive to metabolic alterations, potentially regulating the temporal response to stress or the onset of human diseases such as cancer.

Our group investigates the mechanisms by which RNA modifications regulate protein synthesis and how these mechanisms affect cell fate decisions such as cell proliferation, survival, and differentiation in cancer and stress conditions. By integrating RNA biology, transcriptomics, and cell biology, we aim to uncover novel mechanisms of gene expression regulation and generate new tools that can be harnessed to develop anti-cancer therapies.

For more information, see Dr. Arango's faculty profile and laboratory website.

Current Projects

  • Mechanisms and regulation of RNA acetylation in cancer cells
  • Regulation of stress response by RNA modifications
  • Targeting RNA-modifying enzymes and RNA modifications for therapeutic purposes

Publications

See Dr. Arango's publications.

Contact

Contact Dr. Arango at 312-503-0732.

 Hossein Ardehali Lab

Role of mitochondria and metabolic processes in cancer growth, cardiac disease and immunological processes

 

Research Description

Our lab focuses on three major areas of research:

Role of hexokinase enzymes in immune function, cancer growth and stem cell differentiation

Hexokinase (HK) enzymes phosphorylate glucose to trap it inside the cell. There are 5 mammalian HKs (named HK1-5), with two of them having a hydrophobic region at their N-terminus that allows them to bind to the mitochondria. We have made mouse models and developed in vitro systems to allow us to study the role of mitochondrial binding of HKs in glucose metabolism. We have determined that HK1 binding to the mitochondria determines whether glucose is used for anabolic processes (ie, pentose-phosphate pathway) or catabolism (ie, glycolysis). Thus, the non-enzymatic function of this protein and its subcellular location determines the fate of glucose. We are now studying this process in T-cells, vascular cells and cancer cells. We are also in the process of generating several mouse models of hexokinase enzymes, including HK2 without the mitochondrial binding domain and HK3 knockout mice. We will study these models in different disease and physiological conditions.

Characterization of cellular and mitochondrial iron regulation

Our lab has identified a novel mitochondrial protein, ATP-Binding Cassette-B8 (ABCB8), which plays a role in mitochondrial iron homeostasis and mitochondrial iron export. Mice with ABCB8 knocked out in the heart develop cardiomyopathy and mitochondrial iron accumulation. In addition, we have shown that a pathway involving mTOR and tristetraprolin, treatment with doxorubicin (an anticancer drug that also causes cardiomyopathy) and SIRT2 protein also impact cellular and/or mitochondrial iron regulation. Current studies in this area include: 1) further characterization of ABCB8 in iron homeostasis in other organs and disorders, 2) characterization of the mechanism for iron regulation by SIRT2, 3) identification of the mechanism by which mTOR is regulated by iron through epigenetic changes, 4) role of iron in viral infection, particularly HIV, 5) characterization of the effects of iron on mitochondrial dynamics and 6) identification of novel mitochondrial-specific iron chelators.

Role of mRNA-binding proteins in cellular and systemic metabolism

TTP is a protein that binds to AU-rich regions in the 3’ UTR of mRNA molecules and causes their degradation. It has been studied extensively in the field of inflammation. We recently showed that it also plays a role in cellular iron conservation. We have also shown that TTP is a key mediator of cellular metabolic processes. Our studies have demonstrated that TTP regulates glucose, fatty acid and branched-chain amino acid metabolism in the liver and muscle tissue. We also have evidence that TTP directly regulates mitochondrial electron transport chain (ETC) by targeting specific proteins in the ETC complexes. Finally, recent studies demonstrated that TTP also regulates systemic metabolism by targeting FGF-21 expression. We have both TTP Floxed mice (for the generation of tissue specific TTP knockout mice) and TTP knockout mice in the background of TNF-alpha receptor 1/2 knockout mice (to reduce the inflammatory burden).  Current studies include: 1) role of TTP in liver metabolism of fatty acids and glucose, 2) effects of TTP on mitochondrial proteins, 3) mechanism of TTP regulation of branched-chain amino acid levels and 4) role of TTP in cardiac metabolism.

For more information, see Dr. Ardehali's faculty profile.

Publications

See Dr. Ardehali's publications in PubMed.

Contact

Dr. Ardehali

 Issam Ben-Sahra Lab

Decoding connections between signaling and metabolic networks

Research Description

The Ben-Sahra lab seeks to identify novel connections between oncogenic and physiological signals and cellular metabolism. My previous studies revealed new connections between mTORC1 (mechanistic Target of Rapamycin Complex I) signaling and de novo nucleotide synthesis pathways.

Using isotopic tracing experiments and genetic approaches, my lab investigates whether the additional signaling pathways such as PI3K/Akt, RAF/Erk, Hippo/Yap or AMPK could regulate metabolic pathways that supply small metabolites to sustain nucleotide synthesis independently of mTORC1 signaling. Furthermore, we are also interested in understanding how cells can sense changes in nucleotide levels. In addition to nucleotide metabolism, we also study connections between signaling pathway and global cancer cell metabolism. I predict that there could be points of regulations which could give selective advantages to cancer cells to grow and proliferate. The initial discovery that cancer cells exhibit atypical metabolic characteristics can be traced to the pioneering work of Otto Warburg, over the first half of the twentieth century.

Deciphering the interplay between oncogenic processes and metabolic pathways that contribute to metabolic reprogramming in a given setting may serve as a critical factor in determining therapeutic targets that yield greatest drug efficacy with marginal harmful effect on normal cells. Our research will enable further progress in the exploitation of unusual metabolic features in cancer as a means of therapeutic intervention.

For lab information and more, see Dr. Ben-Sahra's faculty profile and lab website.

Publications

See Dr. Ben-Sahra's publications on PubMed.

Contact

Contact Dr. Ben-Sahra.

 Marcelo Bonini Lab

Understanding the molecular links between aging and cancer

Research Description

Our laboratory is focused on understanding how the declining of metabolic performance with aging changes biophysical cellular parameters relevant for the regulation of gene expression. In particular, we are focused on the hypothesis that an increase in the production of reactive oxygen species by "short-circuited" mitochondria modifies the redox microenvironment of the nucleus changing chromatin structure, compaction and interactions with transcription factors. Based on this idea we aim at developing new first in class therapeutics with ROS modulating function that are targeted to specific organelles. Examples of projects in the laboratory include:

Regulation of EMT by mitochondria ROS - In this project we explore how changes in the nuclear redox state activates (or prevents shutting down) of epithelial-to-mesenchymal transition (EMT) genes. While EMT is essential for development, tissue remodeling and healing, persisting EMT may promote cancer progression and metastasis. We propose that persistent changes to the redox state of the nucleus prolong EMT and facilitates malignant transformation particularly in elderly patients prone to experience declines in mitochondrial performance. 

Pollution by heavy metals and cancer - Lower income populations around the world are disproportionally more exposed to pollution by heavy metals than wealthier communities. A recent example was drinking water pollution by lead in Flint, Michigan. We found that heavy metals promote mitochondrial dysfunction mimicking the process of aging. As such heavy metals promote the dysregulation of gene expression via redox mechanisms. This project is important because it may enable the development of short term pharmacologic solutions for environmental health inequalities issues likely to be aggravated by wars and climate change. 

Redox regulation of inflammatory gene expression - The recent COVID crisis has put in full display the increased susceptibility of elderly patients to infection-induced hyper-inflammatory states. We propose that the accumulation of oxidants in the nucleus of macrophages (immune cells that regulate inflammation) increases the accessibility of pro-inflammatory genes while disabling the transcription of anti-inflammatory ones involved in inflammation resolution and tissue healing. This project is relevant because it may indicate novel mechanisms that can be targeted to "rejuvenate" innate immune cells to react appropriately against pathogens.  

Publications

View lab publications via PubMed

For more information, please see Dr. Bonini's faculty profile 

Contact Us

Email Dr. Bonini

 

 Irina Budunova Lab

Studying the role of the glucocorticoid receptor in carcinogenesis  and stem cell maintenance. Involved in development GR-targeted therapies in skin.

Research Description

The current projects in Dr. Budunova’s lab are centered on the role of the glucocorticoid receptor (GR) as a tumor suppressor gene in skin. We showed that skin-specific GR transgenic animals are resistant to skin carcinogenesis and GR KO animals are more sensitive to skin tumor development.  We are also interested in the role of GR in the maintenance of skin stem cells (SC). We found that GR/glucocorticoids inhibit the expression of numerous SC markers in skin including CD34- a marker of hair follicular epithelial SC and reduce the proliferative potential of skin SCs.

The glucocorticoids remain among the most effective and frequently used anti-inflammatory drugs in dermatology. Unfortunately, patients chronically treated with topical glucocorticoids, develop side effects including cutaneous atrophy. GR controls gene expression via (i) transactivation that requires GR dimerization and binding as homo-dimer to gene promoters and (ii) transrepression that is chiefly mediated via negative interaction between GR and other transcription factors including pro-inflammatory factor NF-kB. In general, GR transrepression is the leading mechanism of glucocorticoid anti-inflammatory effects, while many adverse effects of glucocorticoids are driven by GR transactivation.

Our laboratory has been involved in delineation of mechanisms underlying side effects of glucocorticoids in skin. Using GRdim knockin mice characterized by impaired GR dimerization and activation, we found that GR transactivation plays an important role in skin atrophy. These data suggested that non-steroidal selective GR activators (SEGRA) that do not support GR dimerization, could preserve therapeutic potential of classical glucocorticoids but have reduced adverse effects in skin.  We are testing effects of the novel SEGRA called Compound A– a synthetic analog of natural aziridine precursor from African bush Salsola Botch in skin. We have also established anti-cancer GR-dependent activity of Compound A in epithelial and lymphoma cells.

Using knockout mice for the major GR target genes including Fkbp5 (GR chaperone) and DDIT4/REDD1 (one of the major negative regulators  of mTORC), we discovered that blockage of Fkbp5 and REDD1 significantly changes GR function and greatly protects skin against glucocorticoid-induced atrophy. This suggests a novel GR-targeted anti-inflammatory therapy where glucocorticoids are combined with inhibitors of GR target genes.

For more information, please see Dr. Budunova’s faculty profile.

Publications

See Dr. Budunova's publications in PubMed.

Contact Budunova Lab

Contact the Budunova Lab at 312-503-4669 or visit in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-015, Chicago, IL 60611

Faculty

Irina Budunova, MD, PhD

Research Associates

Pankaj Bhalla, PhDGleb Baida, PhDAnna Klopot, PhD

 Serdar Bulun Lab

Estrogen metabolism in breast cancer, endometriosis and uterine fibroids.

Research Description

The laboratory research of Serdar E. Bulun, MD, focuses on studying estrogen biosynthesis and metabolism, in particular aromatase expression, in hormone-dependent human diseases such as breast cancer, endometriosis and uterine fibroids.

A team of investigators works on understanding the epithelial-stromal interactions and aromatase overexpression in breast cancer tissue. Because aromatase inhibitors treat breast tumors primarily via suppressing intratumoral estrogen biosynthesis, these efforts are important for discovering new targets of treatment.

Another team studies endometriosis. Basic data from this laboratory led to the introduction of aromatase inhibitors into endometriosis treatment. Human tissues and a primate model are used to elucidate cellular and molecular mechanisms responsible for the development of endometriosis.

Regulation of aromatase expression is also studied in uterine fibroids, benign tumors that are dependent on estrogen for growth, by a third team. 

A fourth team is investigating the link between progesterone action and estrogen inactivation in normal endometrium and endometriosis.

Lastly, a fifth team has identified novel mutations that cause familial excessive estrogen formation syndrome. This syndrome is characterized by short stature, gynecomastia and hypogonadism in males and early breast development and irregular menses in females. In this syndrome, heterozygous inversions in chromosome 15q21, which cause the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in estrogen excess owing to the overexpression of aromatase in many tissues.

For more information, please see Dr. Bulun's faculty profile.

Publications

See Dr. Bulun's publications in PubMed.

Contact

Dr. Bulun

 Navdeep Chandel Lab

The Chandel Lab studies the mitochondria as a signaling organelle; using reactive oxygen species as the primary signal for metabolic adaptation, differentiation and proliferation.

Historically, reactive oxygen species (ROS) have been thought to be cellular damaging agents, lacking a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer and premature aging. This guilt by association relationship left a picture of ROS as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution. It appears that oxidative metabolism is no different. More and more evidence suggests that low levels of ROS are critical for healthy cellular function. This idea was first proposed in the mid-1990s when low levels of hydrogen peroxide (H2O2) were demonstrated to be important for cellular signaling. Although mitochondria were known to produce H2O2, NADPH oxidases (NOXs) were the subject of early study due to their well-described role as ‘dedicated H2O2 producers’ in phagocytes. We provided early evidence in the late 1990s that mitochondria release H2O2 to regulate the transcription factor hypoxia inducible factor 1 (HIF-1) (i.e. oxygen sensing). Subsequently, we showed that mitochondrial release of H2O2 can activate p53 and NF-κB. We have recently demonstrated that mitochondria-generated H2O2 can regulate other physiological processes including stem cell differentiation, adaptive immunity and replicative life span of mammalian cells. Furthermore, we have shown that cancer cells co-opt mitochondria-generated H2O2 to hyper-activate signaling resulting in tumor cell proliferation. There have been numerous reports from other laboratories in the past decade also highlighting the importance of mitochondrial H2O2-dependent signaling in metabolic adaptation, immunity, differentiation, autophagy and organismal longevity. We propose that mitochondrial release of H2O2 has evolved as a method of communication between mitochondrial function and other cellular processes to maintain homeostasis and promote adaptation to stress.

Publications

See Dr. Chandel's publications in PubMed.

For more information, please see Dr. Chandel's faculty profile or visit the Chandel Lab website.

Contact Us

Contact Dr. Chandel’s Lab at 312-503-1792

Lab Staff

Lauren Diebold
Graduate Student

James Eisenbart
Lab Manager

Manan Mehta
Graduate Student

Colleen Reczek, PhD

Inma Reyes, PhD

Arianne Rodriguez
Graduate Student

Sam Weinberg
Graduate Student

 Peiwen Chen Lab
Studying tumor-immune symbiotic interactions and developing novel immunotherapies

My laboratory focuses on characterizing the molecular mechanisms that underlie heterotypic interactions across diverse cell types (e.g., cancer cell, immune cell and endothelial cell) in glioblastoma and brain metastatic tumors, and developing novel therapeutic strategies intercepting these co-dependencies. We take an integrated strategy combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analyses to:

(1) study how genetic and epigenetic regulation of cancer cells and/or cancer stem cells can shape an immunosuppressive tumor microenvironment;

(2) elucidate the mechanisms for how these infiltrating immune cells affect tumor growth and brain metastasis;

(3) understand how this tumor-immunity symbiosis affects the effectiveness of cancer therapies, including immunotherapy, anti-angiogenic therapy and conventional therapies, thus developing novel and effective combination therapies.

For more information, please visit the Chen Lab webpage.

 Cheng Lab

Dr. Cheng’s lab investigates cancer stem cell biology, cellular signaling and therapy responses in human brain tumors, particularly glioblastoma (GBM).

Research Description

Our lab broadly studies cancer stem cell biology, cellular signaling, RNA biology, and therapy responses in human brain tumors, in particular, glioblastoma (GBM). We have a range of different projects currently underway in glioma cell lines, gliomas stem-like cells (GSCs), patient-derived xenograft (PDX) GBM model, human iPSC-derived glioma organoid model, orthotopic glioma xenograft model in mice, and clinical glioma tumor specimens. Our current research focuses on novel mechanisms/cellular signaling of GSC biology, tumorigenesis, progression, and therapy responses of GSCs and GBMs.

Roles of RNA alternative splicing and RNA-binding proteins in glioma

RNA alternative splicing (AS), an evolutionarily conserved co-transcriptional process, is an important and influential determinant of transcriptome and proteome landscapes in normal and disease states such as cancer. AS is regulated by a group of RNA binding proteins (RBPs) that bind to the cis-acting elements in proximity to a splice site thus affecting spliceosome assembly. In cancers, altered expression of or mutations in RBPs result in dysregulated AS that impacts cancer biologic properties. We have established AS/RBP networks that are dysregulated in both adult and pediatric gliomas through bioinformatic analysis of both public and our own datasets of clinical glioma tumors. We are investigating the biological significance of AS/RBPs dysregulation in glioma progression and therapy response by using human iPSC-derived glioma organoid model and GSC brain xenograft models in animals. In addition, we are exploring novel therapeutic approaches of targeting glioma-associated AS/RBP networks to treat GBMs.

Roles of Non-coding RNAs in glioma 

Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), act as transcription repressors or inducers of gene expression or functional modulators in all multicellular organisms.  Dysregulated ncRNAs plays critical roles in cancer initiation, progression and responses to therapy. We study the mechanisms by which deregulated expression of lncRNAs or circRNAs influence GBM malignant phenotypes through interactions with signaling pathways. We study the molecular consequences and explore clinical applications of modulating ncRNAs and related oncogenic signaling pathways in GBM.  We are establishing profiles of ncRNAs in clinical gliomas and patient-derived GSCs, and study mechanisms and biological influences of these ncRNAs in regulating GSC biology and GBM phenotypes. 

Aberrant DNA and RNA structures in therapy-resistant GBM

Standard of care treatment for GBM includes the DNA damaging agent temozolomide (TMZ), which has a known mechanism of action to target and mutate guanine bases. With this knowledge in hand, we sought to determine the effects of guanine (G) mutations in DNA and RNA secondary structure. G’s are important for creating structures like g-quadruplexes in both DNA and RNA which can affect changes in translation or be used as docking sites for DNA repair and RNA binding proteins. Using whole genome sequencing data along with isogenic drug sensitive and resistant lines, we are investigating the role of G mutations in DNA and RNA secondary structure to determine potential therapeutic avenues with the help of a chemical biologist to create novel drugs to target these TMZ-induced aberrant pathways.

Targeting autophagy to treat glioma

Autophagy is an evolutionarily conserved process that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism, thus serving as a protective mechanism against stressors and diverse pathologies including cancer. We study mechanisms by which phosphorylation, acetylation and ubiquitination of autophagy-related proteins regulate GSC and GBM phenotypes and autophagic response, which, in turn contributes to tumor cell survival, growth and resistance to therapy. We investigate whether disruption of these post-translational processes in autophagy-related proteins inhibits autophagy and enhances the efficacy of combination therapies in GBMs. In collaboration with a medicinal chemist, we are characterizing a next generation of novel autophagy inhibitors that specifically target a key autophagy regulator that we recently reported.

Multi-omics and GBM non-responsiveness to immunotherapies

GBM is categorized as a “cold” tumor that does not respond to current immunotherapies using various immune-checkpoint blockers. Although extensive efforts have been made to sensitize GBM to immunotherapies, the mechanistic studies to determine alternative therapies from understanding the underlying signaling and clinical trial results are still disappointing. We are interested in utilizing the information of multi-omics of clinical gliomas, in particular, proteomics profiling in relation to genomic and epigenomic profiling, to identify potential protein targets that could be the major modulators through post-translational modifications in these “cold” GBM tumors. We will also consider the involvement of tumor microenvironment and immune cells in these conditions. These studies are a brand-new direction that are high-risk and high-reward to turn “cold” GBM tumors to immunotherapy responsive tumors.

For more information, please see Dr. Cheng's faculty profile and lab website.

Publications

View Dr. Cheng's complete list of publications in PubMed.

Contact Us

Shi-Yuan Cheng, PhD at 312-503-5314

Visit us on campus in the Lurie Building, Room 6-119, 303 E Superior Street, Chicago, Illinois 60611.

 

 Lillian Eichner Lab

Transcriptional dependencies in cancer at the intersection of epigenetics, signaling and metabolism

Research Description

The Eichner lab studies transcriptional dependencies in cancer development, progression and resistance mechanisms. We endeavor to elucidate in vivo transcriptional dependencies at the intersection of epigenetics, signaling, and metabolism to reveal and harness therapeutically targetable transcriptional vulnerabilities in cancer.

Project 1

LKB1 (STK11) is among the most frequently mutated genes in Non-Small Cell Lung Cancer (NSCLC), where it is inactivated in about 20 percent of cases. Leveraging immune-competent genetically engineered mouse models to answer key questions in vivo, our work has revealed key insights into the molecular mechanisms driving this disease. We have identified that transcription plays an important and previously underappreciated role in mediating LKB1 function. Future work will continue utilizing mechanistic understanding to explore novel in vivo transcriptional dependencies and therapeutic liabilities of LKB1 mutant tumors.

Project 2

We have identified critical roles of the druggable epigenetic regulator Histone Deacetylase 3 (HDAC3) in lung tumors. We found that HDAC3 directly represses the secretory component of the cellular senescence program, the SASP, and restrains recruitment of T-cells into tumors in vivo. Future work will continue defining the molecular mechanisms mediating HDAC3’s contribution to tumorigenesis, and further explore epigenetic regulation of the senescence program.

For lab information, publications and more, see Dr. Eichner's faculty profile and laboratory website.

Publications

See Dr. Eichner's publications on PubMed.

Contact

Contact Dr. Eichner.

 Elizabeth Eklund Lab

The Eklund lab investigates myeloid leukemia and approaches to chemotherapy resistant disease.

Dr. Eklund’s laboratory studies are focused on understanding the molecular events that lead to development of myeloid leukemias (acute myeloid leukemia and chronic myeloid leukemia) and to the evolution of drug resistance in these diseases.  The goal is to identify potential molecular therapeutic targets that would delay or prevent drug resistance and relapse in AML and CML.  In related projects, the laboratory is investigating Fanconi Anemia, a genetic disease with defective DNA repair.  Patients with Fanconi Anemia frequently develop leukemia and provide a model for understanding the role of DNA repair in leukemogenesis.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Elizabeth Eklund, MD.

Contact Us

Contact Dr. Eklund at 312-503-3208 or the Eklund Lab at 312-503-3208.

Lab Staff

Ling Bei, MD
Research Associate
312-503-3206

Elizabeth Hjort
Graduate Student
312-503-4642

Liping Hu, PhD
Post Doctoral Fellow
312-503-4642

Weigi Huang, MD
Research Assistant Professor
312-503-3206

Chirag Shah, PhD
Research Associate
312-503-4642

Hao Wang, PhD
Research Assistant Professor
312-503-3204

 Cara Gottardi Lab

The Gottardi Lab investigates how cells adhere to each other and how this adhesion is regulated and controls gene expression in heath and disease.

The ability of individual cells to adhere and coalesce into distinct tissues is a major feature of multicellular organisms. Research in my laboratory centers on a protein complex that projects from the cell surface and forms a structural “Velcro” that holds cells to one another. This complex is comprised of a transmembrane “cadherin” component that mediates Ca++-dependent homophilic recognition and a number of associated “catenins” that link cadherins to the underlying cytoskeleton.  A major focus in our lab is to understand how these catenins direct static versus fluid adhesive states at the plasma membrane, as well as gene expression and differentiation in the nucleus. These basic questions are shedding new light on how dysregulation of the cadherin/catenin adhesion system drives pathologies such as asthma, fibrosis and cancer.

Publications

See Dr. Gottardi's publications in PubMed.

For more information, please see Dr. Gottardi's faculty profile.

Lab Staff

Annette Flozak
Research Technologist
312-503-0409

 

 Yogesh Goyal Lab

Single-Cell Biology of Development and Disease

Research Description

We are interested in understanding the control principles governing biological processes at various scales, from tissue morphogenesis in development to cell-fate decisions in single cells. In particular, individual cells within a genetically identical population constantly undergo fluctuations in their molecular state which may enable them to adopt new fates in response to stimuli. As opposed to hardwired responses encoded in the genome, this dynamic ability of cells to react, either alone or in concert with each other, to external and internal cues is broadly referred to as “plasticity”. Leveraging our unique interdisciplinary approach, we combine novel frameworks, both experimental (e.g. single-cell profiling, spatiotemporally-resolved lineage tracing, multiplexed single-molecule RNA imaging, optogenetics) and computational (stochastic modeling, statistical analysis of large datasets), to track and control state-to-fate mappings in the context of animal development and cancer progression. Working across multiple mammalian model systems (cell lines, developmental and tumor organoids, mouse models), we will ask how diverse non-genetic variabilities drive fate choices and self-organization in development and disease.

To learn more about specific projects, please visit our Lab Website.

 

Publications

See the Goyal Lab’s publications on the Goyal Lab Website.

Contact

Dr. Goyal.

 Xiaolin He Lab

Mechanisms of signal transmission across the membrane via the cell-surface receptors

Research Description

This laboratory is interested in cancer, neural development and reproduction-related structural mechanisms of how extracellular signals (e.g., growth factors, adhesion molecules and morphogens) are translated into intracellular signals by plasma membrane receptors. We use biophysical methods (crystallography, calorimetry, surface plasmon resonance, analytical ultracentrifugation, etc.) in combination with functional studies to define the physiological states and binding processes of these receptors and their complexes with ligands. Our research targets include receptor tyrosine kinases, Semaphorin and its receptors and leucine-rich-repeat-containing G-protein coupled-receptors.

For more information, visit the faculty profile of Xiaolin He, PhD.

Publications

See Dr. He's publications in PubMed.

Staff Listing

Research Associate:
Xiaoyan Chen

Graduate Student:
Po-Han Chen

Contact Us

Contact Dr. He at 312-503-8030 or the He Lab at 312-503-8029.

 Amy Heimberger Lab

Improving the lives of patients with central nervous system (CNS) cancers through the development of new immunotherapies informed by understanding the underlying unique immunobiology of the CNS. 

Research Description

Our laboratory studies the unique immunobiology of CNS tumors that informs our development of immuno-oncology therapeutics. The laboratory has been intricately involved in a wide variety of bench-to-bedside immune therapeutics, including those that developed in the laboratory and arising from our own patents. We work collaboratively with industry on their pipeline agents to clarify indications and companion biomarkers. The laboratory carries unique expertise in the investigational new drug process and window-of-opportunity clinical trials. The laboratory conducts extensive immune profiling of patient tumors including ex vivo functional assays. Our studies are directed to how various cells interact within the tumor microenvironment and the functional implications using multiplex imaging, methylation profiling, single cell sequencing and transcriptomic analysis. Areas in which we have contributed to science include the following:

EGFRvIII peptide vaccines Our laboratory co-developed with Duke University from bench-to-bedside a peptide (PEP-3-KLH/CDX-110) vaccine strategy that targets the epidermal growth factor receptor (EGFRvIII), that demonstrated induction of anti-tumor immune responses.

 STAT3 mediated immune suppression and therapeutic targeting We clarified that the signal transducer and activator of transcription 3 STAT3 pathway is a key molecular hub of gliomagenesis and tumor-mediated immune suppression and conducted the preclinical development of a novel small molecule inhibitor of STAT3, WP1066, for which I hold the IND. STAT3 has been considered an “un-druggable” target and this is a first-in-man agent with specificity to STAT3. This drug has been licensed to Moleculin and is now in clinical trials.

Glioblastoma mediated mechanisms of immune suppression We have demonstrated that glioblastoma subverts the immune system to become tumor protective, especially by 1) driving tumor-associated microglia/macrophages to assist in potentiating gliomagenesis; 2) by recruitment of Tregs; 3) and by the intrinsic properties of cancer stem cells which are immunosuppressive on both adaptive and innate immunity. This investigative direction has provided potential therapeutic targets/strategies and biomarker elucidation.

miRNA and nanoparticle therapeutics The laboratory has elucidated the role of epigenetic microRNA regulation on tumor-mediated immune suppression, with an emphasis on potential translational therapeutic approaches.  One of these strategies, miR-124 delivered with lipid nanoparticles to the immune compartment entered clinical trials in spontaneously arising gliomas in canines. 

Immune checkpoint therapeutics and response biomarkers Given the recent FDA approvals of immune checkpoint inhibitors for malignancies, there is great enthusiasm for their use in glioblastoma. Recent work in our lab has been focused on clarification of potential response biomarkers and identification of GBM patient subsets that may benefit.

For more information, please visit the Amy Heimberger Lab page

 

 Dai Horiuchi Lab

Understanding the cellular events that influence the aggressiveness of tumors and patient clinical outcome

Research Description

The major focus of the Horiuchi lab, established on April 1, 2015, is on the mechanisms of tumor maintenance and progression in breast cancer and to identify novel therapeutic targets and treatment strategies. To achieve these goals, we utilize a collection of human breast cancer cell lines, preclinical animal models and high-throughput screening approaches along with state-of-the-art bioinformatics through collaboration with experts in the field.

We are currently focused on the following areas:

  1. Mechanisms of tumor maintenance and progression medicated by proto-oncogenes (i.e., MYC transcription factor, PIM family of serine/threonine kinases, etc.), their activators and effectors and the tumor microenvironment.
  2. Biology and therapeutic targetability of novel molecular factors that determine patient clinical outcome.

For lab information and more, see Dr. Horiuchi’s faculty profile.

Publications

See Dr. Horiuchi's publications on PubMed.

Contact

Contact Dr. Horiuchi at 312-503-4085 or the lab at 312-503-4349.

Lab Staff

Technical Staff

Lauren Begg, Adrienne Orriols

 Peng Ji Lab

Role of MDia1 in the pathogenesis of del(5q) myelodysplastic syndromes

Research Interests

Our lab is interested in how cytoskeletal signaling, motor proteins and adhesion systems are integrated with chemical signaling pathways to regulate cell behavior and tissue differentiation and disease. The Ji lab studies small G proteins and downstream actin regulatory effectors that participate in enucleation during red cell development.

At the level of the nucleus, the Ji laboratory studies genes involved in erythroid lineage commitment, chromatin condensation and enucleation towards understanding how congenital red cell disorders and leukemia develop. 

For more information, visit the faculty profile of Peng Ji, MD, PhD.

Publications

See Dr. Ji's publications in PubMed.

Contact

Dr. Ji

 Julie Kim Lab

The role of progesterone receptor in uterine diseases

Research Description

Progesterone is essential for the regulation of normal female reproductive function.  Its mode of action is diverse and dependent on the target tissues.  In my lab we are interested in delineating the molecular mechanisms of progesterone action through its receptor, PR in the uterus.  This is done in the context of normal endometrial differentiation, specifically, decidualization, as well as in uterine pathologies, such as endometriosis, endometrial cancer and uterine fibroids.  Interestingly, in these three diseases, progesterone responsiveness is aberrant.

Endometrial cancer is the most common gynecologic cancer diagnosed in the United States with an estimated 40,100 new cases and about 7,500 deaths in 2008.  As risk factors for endometrial cancer increase, the incidence of this disease will also rise, with a paradigm shift to younger ages. In our laboratory, we investigate the role of progesterone receptor in endometrial cancer to understand why progestin therapy is not an effective treatment in all cases of endometrial cancer.

Endometriosis is an estrogen-dependent disorder affecting up to 10% of the female population and 30-50% of infertile women, with no cure and limited therapies. It is often associated with debilitating pelvic pain and infertility. This disease has also been referred to as a “progesterone resistant” disease since the ectopic and eutopic tissues do not respond to progesterone as it does in normal endometrial tissues. Our laboratory is investigating progesterone resistance in endometriosis and identifying specific biological targets for the future development of alternative therapies.

Leiomyoma, also known as uterine fibroids, are benign tumors originating from the myometrium. These tumors can range from a few millimeters to over 20 cm in size. Leiomyomas are common and can occur in up to 77% of women while up to 20% of women suffer from significant morbidity, pain and discomfort and excessive menstrual bleeding. Leiomyomas are the primary indication for over 200,000 hysterectomies in the United States. In our laboratory we are investigating how progesterone promotes growth of leiomyomas by focusing on the non-genomic signaling of progesterone on the PI3K/AKT pathway. These studies are translated to the identification of important signaling molecules that can be targeted using small molecule inhibitors.

For more information, please see Dr. Kim's faculty profile or the Kim Lab website.

Publications

See Dr. Kim's publications in PubMed.

Contact

Contact Dr. Kim at 312-503-5377 or the Kim Lab at 312-503-4762.

 Hiroaki Kiyokawa Lab

Investigating the roles of cell cycle-regulatory proteins in differentiation, senescence and tumorigenesis and the cell cycle control in endocrine and reproductive organs

Research Description

We are interested in the basic mechanisms of cell cycle control, cellular senescence/immortalization and malignant transformation, with a focus on protein regulation by ubiquitination. We previously demonstrated that cell cycle regulators such as p27Kip1, CDK4 and CDC25A play highly tissue-specific roles in development and oncogenesis. Ubiquitination, the covalent modification of substrate proteins with the small 76-residue protein ubiquitin, exerts diverse regulation of the fate of substrates, including the cell cycle regulators, e.g, promoting proteolysis, altering subcellular localization and modulating enzymatic activities. Our current research is aimed at revealing novel functions of ubiquitination enzymes and their substrates in development and cancer, which is expected to identify new therapeutic targets against human diseases. The laboratory uses a combination of protein engineering, proteomics, bioinformatics, cell biological techniques such as time-lapse microscopy and 3-D culture and genetically engineered mouse models. Keywords: cell cycle, ubiquitin, ubiquitination, cancer initiation, cancer progression, knockout mice, transgenic mice, breast cancer, cyclin, diabetes, pituitary, development.

Recent Findings

  • There is a unique regulation of cell cycle progression in neuroendocrine tissues such as pancreatic islets and pituitary glands of CDK4-null mice; we have shown that in this particular type of cell cycle, Cdk4 plays an indispensable and rate-limiting role
  • CDC25A phosphatase, which activates CDK2 and CDK1, is an oncogene that plays a rate-limiting role in initiation and progression of various tumors, including breast cancer

Current Projects

We are currently investigating roles of the cell cycle machinery in differentiation, tumorigenesis and apoptosis, by combinations of mouse models and molecular analyses.

For lab information and more, see Dr. Kiyokawa’s faculty profile.

Publications

See Dr. Kiyokawa's publications on PubMed.

Contact

Contact Dr. Kiyokawa at 312-503-0699.

Lab Staff

Technical Staff

Cade Brittain, Alison Rogozinski

Temporary Staff

Asia Owais

 Shannon Lauberth Lab

Decoding the Cancer Epigenome

Research Description

The Lauberth Lab is located in the department of Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine and is located in the Simpson Querrey Biomedical Research Center on Northwestern’s campus in downtown Chicago.

Our primary research focus is to make advances in basic and translational studies in the cancer epigenetics field. The laboratory utilizes a combination of approaches that include cutting-edge high-throughput NGS technologies, state of the art microscopy techniques, quantitative proteomics, biochemistry, and cell-based/genetic assays. We also employ powerful cell-free assays that fully reconstitute transcription on chromatin templates and are powerful in discerning direct (causal) effects of epigenetic and transcriptional regulatory mechanisms.

Current Projects

The general transcription machinery functions as signal transducers

Through an exciting collaboration with Nullin Divecha’s group (University of Southampton), we discovered a new role of the basal transcription TFIID complex component, TAF3 in transducing nuclear phosphoinositide signals into gene expression changes that are required to build muscle tissue. This work was published in Molecular Cell.

p53 mutant enhancer selection and regulation imparts transcriptional plasticity to cancer cells in response to chronic immune signaling

My lab has made important contributions in revealing mechanistic insights into how chronic immune signaling drives alterations in the cancer cell transcriptome. We have demonstrated a functional crosstalk between the second most frequently identified p53 mutant and the master proinflammatory regulator NFkB that shapes an active enhancer landscape to reprogram the cancer cell transcriptome in response to chronic TNFa signaling. These studies also revealed insights into mutant p53-dependent gene regulation by describing new ways in which mutant p53 is recruited to specific classes of enhancers through various binding partners since mutant p53 does not directly engage with DNA. This new mechanism underlying the tumor-promoting roles of mutant p53 was published in Nature Communications.

Mutant p53 Co-Opts Chromatin Pathways at Enhancers to Drive Cancer Cell Growth

Our studies have advanced our understanding of cancer epigenetics by establishing an interplay between p53 mutants and chromatin regulators that leads to aberrant enhancer and gene activation in human cancer. Specifically, through global analyses, we demonstrated a requirement for mutant p53 in regulating the prominent histone mark, monomethylation of histone H3 lysine 4 (H3K4me1) that demarcates enhancer regions. This is an important finding that provides new mechanistic insights into how H3K4me1 levels are altered, which is a frequent event in various human cancers. Also, by implementing cell-based and our unique cell-free assays, we revealed mechanistic insights into the cooperativity between epigenetic regulators, MLL4 and the histone acetyltransferase p300 in promoting joint epigenetic aberrations that support enhanced transcriptional activation by mutant p53. These important findings were published in the Journal of Biological Chemistry.

eRNAs regulate the expression of tumor promoting genes

Our recent research efforts have resulted in new insights into the functions of eRNAs, which is particularly significant since these findings are among the few studies to date that have identified roles for these noncoding transcripts. Through global profiling analyses, we identified eRNAs that are synthesized by various p53 mutants, and by depleting several of these eRNAs, we identified their direct roles in the regulation of tumor promoting gene expression. We also revealed that these eRNAs function through the chromatin recognition bromodomains (BDs) of the extra-terminal motif (BET) family member BRD4. We further characterized a mechanism in which eRNAs are required to increase BRD4 binding to acetylated histones and promote enhanced BRD4 and RNAPII recruitment at specific enhancers that, in turn augments enhancer and tumor promoting gene activation. We also extended the implications of our findings by revealing that the BDs of all BET family members and several non-BET family members also directly interact with eRNAs. These findings provide a previously unrecognized convergence between eRNAs and histone posttranslational modifications in regulating the binding of chromatin reader proteins and highlight a mechanism in which eRNAs play a direct role in gene regulation by modulating chromatin interactions and transcription functions of BRD4. A manuscript describing these findings has been published in Nature Structural & Molecular Biology (NSMB).

We have also published several reviews on enhancer regulation and function and the mechanisms underlying eRNA functions that you can find by viewing our publications.

For more information, please see Dr. Lauberth's faculty profile and laboratory website.

Select Publications

Ohguchi H, Park PMC, Wang T, Gryder BE, Ogiya D, Kurata K, Zhang X, Li D, Pei C, Masuda T, Johansson C, Wimalasena VK, Kim Y, Hino S, Usuki S, Kawano Y, Samur MK, Tai YT, Munshi NC, Matsuoka M, Ohtsuki S, Nakao M, Minami T, Lauberth S, Khan J, Oppermann U, Durbin AD, Anderson KC, Hideshima T, Qi J. Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma. Blood Cancer Discov. 2021 Jul;2(4):370-387. doi: 10.1158/2643-3230.BCD-20-0108. Epub 2021 Apr 10. PMID: 34258103; PMCID: PMC8265280.

Sartorelli, V., Lauberth, S.M. Enhancer RNAs are an important regulatory layer of the epigenome. Nat Struct Mol Biol 27, 521–528 (2020). https://doi.org/10.1038/s41594-020-0446-0

Rahnamoun H, Orozco P, Lauberth SM. The role of enhancer RNAs in epigenetic regulation of gene expression. Transcription. 2020 Feb;11(1):19-25. doi: 10.1080/21541264.2019.1698934. Epub 2019 Dec 11. PMID: 31823686; PMCID: PMC7053929.

Rahnamoun, H., Lee, J., Sun, Z. et al. RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation. Nat Struct Mol Biol 25, 687–697 (2018). https://doi.org/10.1038/s41594-018-0102-0

Rahnamoun H, Hong J, Sun Z, Lee J, Lu H, Lauberth SM. Mutant p53 regulates enhancer-associated H3K4 monomethylation through interactions with the methyltransferase MLL4. J Biol Chem. 2018 Aug 24;293(34):13234-13246. doi: 10.1074/jbc.RA118.003387. Epub 2018 Jun 28. PMID: 29954944; PMCID: PMC6109924.

Rahnamoun, H., Lu, H., Duttke, S.H. et al. Mutant p53 shapes the enhancer landscape of cancer cells in response to chronic immune signaling. Nat Commun 8, 754 (2017). https://doi.org/10.1038/s41467-017-01117-y

Stijf-Bultsma Y, Sommer L, Tauber M, Baalbaki M, Giardoglou P, Jones DR, Gelato KA, van Pelt J, Shah Z, Rahnamoun H, Toma C, Anderson KE, Hawkins P, Lauberth SM, Haramis AP, Hart D, Fischle W, Divecha N. The basal transcription complex component TAF3 transduces changes in nuclear phosphoinositides into transcriptional output. Mol Cell. 2015 May 7;58(3):453-67. doi: 10.1016/j.molcel.2015.03.009. Epub 2015 Apr 9. PMID: 25866244; PMCID: PMC4429956.

Lauberth SM, Nakayama T, Wu X, Ferris AL, Tang Z, Hughes SH, Roeder RG. H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation. Cell. 2013 Feb 28;152(5):1021-36. doi: 10.1016/j.cell.2013.01.052. PMID: 23452851; PMCID: PMC3588593.

Lauberth SM, Bilyeu AC, Firulli BA, Kroll KL, Rauchman M. A phosphomimetic mutation in the Sall1 repression motif disrupts recruitment of the nucleosome remodeling and deacetylase complex and repression of Gbx2. J Biol Chem. 2007 Nov 30;282(48):34858-68. doi: 10.1074/jbc.M703702200. Epub 2007 Sep 25. PMID: 17895244.

Lauberth SM, Rauchman M. A conserved 12-amino acid motif in Sall1 recruits the nucleosome remodeling and deacetylase corepressor complex. J Biol Chem. 2006 Aug 18;281(33):23922-31. doi: 10.1074/jbc.M513461200. Epub 2006 May 17. PMID: 16707490.

View all of Dr. Lauberth's publications on PubMed.

Contact

Contact Dr. Lauberth at 312-503-4780.

Lab Contact Information

Northwestern University Feinberg School of Medicine
Simpson Querrey 7-400B
303 E. Superior Street
Chicago, IL 60611

Lab Staff

Gabriel Lopez
Research Technologist

Jessica Xu
Graduate Researcher

Anita Wang
Lab Coordinator

Nicholas Chin
Temporary Staff

Dylan Jann Pedersen
Temporary Staff

 Isabelle Caroline Le Poole Lab

Immune recognition of melanoma-associated antigens, aiming to develop immunotherapeutics for benign and malignant disease.

Research Description

Role for HSP70i in driving autoimmune responses. This stress protein is included as a component of some anti-tumor vaccines based on its chaperone and adjuvant functions. In human samples, we found that HSP70i is upregulated in vitiligo skin, that HSP70i can associate with melanosomes under stress and that the heat shock protein is increasingly secreted by vitiligo melanocytes.

Development of an immunotherapeutic vaccine for patients with lymphangioleiomyomatosis (LAM). This devastating disease involves development of slow growing tumors in the lungs of female patients with mutations in TSC1 or TSC2. As tumor cells of smooth muscle cell origin transdifferentiate to express melanoma associated antigens, we propose to target melanosomal antigens using T cell receptor transgenic, autologous T cells.

Development of a chemopreventive approach towards melanoma.  The concept carries similarity to ‘elective surgery’ available for some other cancers. This strategy is further supported by the immune response that is indirectly elicited by dying melanocytes targeted by topically applied bleaching phenols. We have contributed to elucidating the mechanism by which phenolic agents can induce melanocyte death, expanded the arsenal of reagents to include those which specifically target the stem cell population and studied the immune response that follows.

Restoring tolerance in newly developed mouse models of autoimmune vitiligo.  Contrary to the existing problem of overzealous regulatory responses that interfere with anti-tumor immunity, patients with autoimmune disease activity generally lack effective regulatory responses. So whereas anti-CD25 therapy to deplete Tregs is popular as a pretreatment for patients undergoing anti-tumor immunotherapy, the opposite holds true in autoimmune disease. We propose to manipulate Treg homing in particular, and recently demonstrated elevated CCR4 expression in circulating Treg from melanoma patients whereas its ligand is highly expressed in tumors; the opposite holds true in vitiligo.

For more information, see the faculty profile for Dr. Le Poole, PhD.

Email Dr. Le Poole.

 Xiao-Nan Li Lab

Understanding tumor biology and implementing preclinical drug testing of malignant brain tumors

Research Description

Our research work focuses on molecular neuro-oncology and experimental therapeutics of malignant brain tumors.  Our goal is to develop more effective and less toxic therapies for children with malignant brain tumors to significantly improve the clinical outcomes.  1) Clinically relevant and molecularly accurate animal models: We have optimized a protocol for to implant a patient’s tumor cells directly into the matched location in mouse brains.  Our laboratory has developed >130 patient derived orthotopic xenograft (PDOX or orthotopic PDX) models of pediatric brain tumors, including high-grade glioma/glioblastoma (GBM), medulloblastoma (MB), ependymoma (EPN), diffuse intrinsic pontine glioma (DIPG), atypical teratoid/rhabdoid tumor (ATRT), Embryonal tumors with multilayered rosettes (ETMR), CNS germinoma, and pleomorphic xanthoastrocytoma (PXA), as well as ~20 models of adult GBM and meningioma. 2) All the models are subjected to detailed histopathological and comprehensive molecular characterizations through global gene expression (RNAseq, single cell RNAseq), whole genome sequencing, DNA copy number analysis, whole genome DNA methylation analysis during serial in vivo subtransplantations to confirm thee cellular and molecular fidelities of the patient-specific PDOX models.  3) Recognizing the need of in vitro model system, we are also utilizing our PDOX model system to develop long term cultures/cell lines as monolayer, 3D neurospheres and organoids. 4) Using this unique in vitro and in vivo model system, we are actively engaged in the understanding of tumor biology and the testing of new therapeutic strategies.

Current Projects

  • Understanding the mechanisms of brain tumor invasion of pediatric GBM
  • Discovery of cellular and molecular drivers of medulloblastoma metastasis
  • Investigating the regulation of cell cycle progression, particularly from quiescent G0 to active G1 phase
  • Implementing unbiased high-throughput combinatory drug screening against highly malignant brain tumors using a novel drug library composed of 17,000 drugs and investigational agents
  • Identifying cellular origins and molecular drivers of therapy resistance and tumor relapse
  • Evaluating therapeutic efficacy and elucidation of mechanisms of action of novel anti-cancer therapies in vivo in PDOX models for the initiation of clinical trials.

For more information, visit the faculty profile of Xiao-Nan Li, MD, PhD.

Publications

See Dr. Li's publications.

Contact

Email Dr. Li

 Huiping Liu Lab

Understanding and targeting cancer stem cells and exosomes in metastasis using cutting-edge technology and novel therapeutics

Liu Lab photo

Research Description

The Liu lab studies the molecular and cellular mechanisms underlying cancer stem cells (CSCs) and metastasis through four ongoing interactive basic and translational research projects: (1) to understand CSCs, circulating tumor cells (CTCs) and their interactions with immune cells in metastasis; (2) to dissect the role of secreted and circulating exosomes in CSC functions; (3) to target CSCs with novel therapeutics, exosomes and nanoparticles in combination with immunotherapy; (4) to develop CTC and circulating exosome-based biomarkers for cancer diagnosis, therapy response and predictive prognosis.

Recent Findings

  1. CSCs seed metastases of breast cancer.
  2. A rapid, automated surface protein profiling of single circulating exosomes in human blood. (PMID: 27819324)
  3. Micro-206 inhibits stemness and metastasis of breast cancer by targeting MKL1/IL11 pathway. (PMID: 27435395)
  4. Differentiation and loss of malignant character of spontaneous pulmonary metastases in patient-derived breast cancer models. (PMID: 25339353)
  5. MicroRNA-30c inhibits human breast tumor chemotherapy resistance by regulating TWF1 and IL-11.(PMID: 23340433)

Current Projects

  1. Identify how CSCs crosstalk between themselves and interplay with immune cells in circulation thus developing innovative anti-CSC targeting therapeutics.
  2. Single cell RNA sequencing of CSCs and metastatic tumors.
  3. Dissect the role of exosomes in CSC functions and regulation of exosome functions by CSCs.
  4. Develop CSC-targeting novel microRNA therapeutics and exosome delivery tools.
  5. Discover CTC and circulating exosome-based clinical biomarkers for cancer diagnosis, treatment monitoring and prognosis.

For lab information and more, see Dr. Liu's faculty profile and lab website.

Publications

See Dr. Liu's publications on PubMed.

Contact

Contact Dr. Liu at 312-503-5248.

Lab Staff

Research Faculty

Yuzhi Jia

Postdoctoral Fellows

Nurmaa Dashzeveg, Lamiaa El-Shennawy, Andrew Hoffmann

Graduate Students

Hannah Mubarak, Emma Schuster, Erika K. Ramos, David Scholten

Visiting Scholars

Valery Adorno-Cruz

 Yan Liu Lab

Hematopoietic stem cell self-renewal and pathogenesis of myeloid malignancies

Research Description

The Liu laboratory is interested in investigating the molecular mechanisms governing normal and malignant hematopoiesis, with an emphasis on understanding hematopoietic stem cell (HSC) self-renewal and pathogenesis of myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Our long-term goals are to identify novel regulators of HSC self-renewal, understand the molecular mechanisms regulating their function, and develop novel therapeutic strategies to eliminate leukemia stem cells (LSCs) and improve leukemia treatment. We utilize molecular, genetic, immunological, biochemical, and pharmacological approaches as well as unbiased genome wide studies, including RNA-seq, ChIP-seq, ATAC-seq, and cytokine arrays, to investigate the molecular basis of HSC self-renewal and leukemogenesis. Major areas of focus include: 1) The role of tumor suppressor p53 in CHIP progression and pathogenesis of MDS; 2) Phosphatase PRL2 in HSC self-renewal and leukemogenesis; 3) Polycomb Repressive Complex 1 (PRC1) in HSC self-renewal and terminal differentiation.

For more information, visit Dr. Liu's faculty profile page.

Publications

View Dr. Liu's publications at PubMed.

Contact

Email Dr. Liu

 

 

 Richard Longnecker Lab

Epstein-Barr virus (EBV) and herpes simplex virus (HSV) entry, replication and pathogenesis.

Research Description

Research in the Longnecker laboratory focuses on herpes simplex virus (HSV) and Epstein-Barr virus (EBV). These viruses typically cause self-limiting disease within the human population but both can be associated with serious complications. EBV is associated with variety of hematopoietic cancers such as African Burkitt lymphoma, Hodgkin Lymphoma and adult T-cell leukemia. EBV-associated lymphoproliferative disease occurs in individuals with congenital or acquired cellular immune deficiencies. The two notable epithelial diseases associated with EBV infection are nasopharyngeal cancer and oral hairy leukoplakia. Similar to EBV, HSV latent infections are very common in humans. HSV typically does not cause severe disease but is associated with localized mucocutaneous lesions, but in some cases can cause meningitis and encephalitis. The Longnecker laboratory focuses on several aspects of EBV and HSV replication and pathogenesis. First, the molecular basis EBV transformation and how it relates to cancer is being investigated. The laboratory is currently screening selective inhibitors that may be beneficial in EBV-associated cancers such as Hodgkin lymphoma, Burkitt lymphoma and proliferative disorders that occur in HIV/AIDS and transplant patients. Second, the laboratory is investigating herpesvirus latency in the human host and pathogenesis associated with infections in humans. In this regard, the laboratory is developing animal models for EBV and HSV infections. Finally, the laboratory is investigating the function of herpesvirus encoded proteins and the cellular receptors that are important for infection both using in vivo culture models as well as animal models. Ultimately, studies by the Longnecker laboratory may provide insight for the development of novel therapeutics for the treatment of herpesvirus infections in humans and better understanding of the herpesvirus life cycle in the human host

For lab information and more, see Dr. Longnecker's faculty profile.

Publications

See Dr. Longnecker's publications on PubMed.

Contact

Contact Dr. Longnecker at 312-503-0467 or the lab at 312-503-0468 or 312-503-9783.

Lab Staff

Research Faculty

Jia Chen, Qing Fan, Kamonwan "Pear" Fish, Masato Ikeda

Adjunct Faculty

Sarah Connolly, Michelle Swanson-Mungerson

Graduate Students

Cooper Hayes, Daniel Giraldo Perez, Seo Jin Park

Technical Staff

Sarah Kopp, Rachel Riccio, Samantha Schaller, Nanette Susmarski

 Nick Lu Lab

The Lu Lab investigates glucocorticoid efficacy and mechanisms of action in asthma and cancer.

Glucocorticoids are the most frequently prescribed medicine today and they are indispensable in the treatment of asthma, inflammation and cancer. However, two concerns regarding glucocorticoid use remain unresolved. One is that high-dose or long-term glucocorticoids result in troublesome side effects such as metabolic syndrome and osteoporosis; the other is that some patients do not respond to glucocorticoids. We tackle both questions by examining the glucocorticoid receptor. Translational isoforms of glucocorticoid receptors were recently discovered in our lab and they provide insights into the mechanisms of action of glucocorticoids. Ribosomal shunting and leaky scanning processes generate translational glucocorticoid receptor isoforms. These receptor isoforms have distinct cell-killing and cytokine-suppression capabilities in a bone cancer cell model system. Currently, we are identifying and characterizing the receptor isoforms in different populations of immune cells in diseases such as asthma and cancer. This line of research has implications in several other fields in addition to immunology and oncology. For instance, our findings in glucocorticoid receptor biology have significant impact on research in endocrinology as well.

Publications

View publications on PubMed

For more information visit the faculty profile of Nick Lu, PhD

Contact

Contact Dr. Lu at 312-503-1310 or the Lu Lab at 312-503-1963.

Lab Staff

Jesus Banuelos, BA
PhD Student
312-503-1396

Yun Cao, MD
Senior Research Technologist
312-503-1396

Soon Cheon Shin, PhD
Research Associate
312-503-1396

 Daniela Matei Lab

Mechanisms of ovarian cancer metastasis and novel therapeutics for ovarian cancer

Research Description

My laboratory studies mechanisms of ovarian cancer metastasis and novel therapeutics for ovarian cancer. The general theme is translation between bench and clinic; with laboratory research forming the foundation for clinical experiments. 

One direction of investigation relates to the interaction between cancer cells and the peritoneal stroma.  We described the functions of tissue transglutaminase as an interacting partner of b-integrins and regulator of peritoneal metastasis.  Based on new mechanistic insight into the roles of this enzyme in ovarian cancer, we discovered and began characterizing new small molecule inhibitors for the transglutaminase-fibronectin-integrin interaction that are being developed as anti-cancer agents. We are studying these new inhibitors in-vitro and in in-vivo models of ovarian cancer metastasis.

Another area of research focusses on the characteristics and therapeutic vulnerabilities of ovarian cancer stem cells.  We used small molecule inhibitors that target ALDH1A1 to block the tumorigenic capacity of these cancer-initiating cells.  We are studying how ALDH1A1 inhibitors alter stem cell specific signaling and how ALDH1A1 is involved in maintaining the cancer stem cell properties. 

More recently we identified new metabolic alterations involving fatty acids desaturation in cancer stem cells.  We have targeted lipid metabolism using small molecule inhibitors and are studying the mechanisms by which these metabolic changes contribute to the maintenance and tumorigenicity of cancer stem cells.  Future goals are to refine the use of ALDH and fatty acid desaturases inhibitors to target cancer stem cells residual after chemotherapy and to eradicate the disease.

Another important direction of investigation is epigenetic modulation as a method of resensitization to platinum in ovarian cancer.  We successfully brought to the clinic the concept that epigenetic modulation re-sensitizes chemotherapy-resistant ovarian tumors to carboplatin.  I led a randomized multi-institutional clinical trial testing the effects of DNA hypomethylating agents and carboplatin compared to standard chemotherapy.  We are now analyzing the genome and epigenome of platinum resistant ovarian cancer using specimens from this trial.  We have identified several pathways that are associated with platinum resistance and respond to hypomethylating agents.  We have designed a new strategy to target pathway-specific DNA methylation and are testing the effects of this intervention on cell signaling and gene expression profiles in ovarian cancer cells.  

Publications

View Dr. Matei's publications on PubMed

Contact

Email Dr. Matei

Phone 312 503-4853

 Marc Mendillo Lab

Cellular stress response systems in malignancies

Research Description

The cellular stress response systems guard the proteome from diverse endogenous and environmental insults to maintain the fitness of the organism. Ironically, this pro-survival system can act to the detriment of the host to enable tumor cells accommodate to the myriad stresses associated with malignancy. Our long-term goals are to identify and characterize the systems that promote protein homeostasis, understand how these systems are co-opted and perturbed in malignancy, and ultimately identify means to manipulate them for therapeutic benefit. To accomplish these goals our group bridges biochemical, genetic and chemical biology approaches with systematic high-throughput and genomic methods.

For lab information, publications and more, see Dr. Mendillo’s faculty profile.

Publications

View Dr. Mendillo's publications at PubMed

Contact

Email Dr. Mendillo

Phone 312-503-5685

 Booki Min Lab

Regulatory T cells in inflammation

Research Description

The immune system is tightly controlled by multiple mechanisms, and Foxp3+ regulatory T (Treg) cells are prominent active regulators of immunity and tolerance. Defects in Treg cell generation or function result in uncontrolled systemic autoimmune inflammation. Despite extensive investigation in Treg cell biology, our understanding the mechanisms underlying Treg cell development and functions still remains incomplete. There is increasing evidence that Treg cell functions can be compromised under certain conditions, and such dysregulation is thought to be a contributing factor of chronic inflammatory conditions. Our laboratory studies both cellular and molecular factors that control Treg cell functions.

There are three major research projects currently underway in the laboratory.

1. IL-27 and Treg cells: Earlier studies had identified that IL-27, an immune regulatory cytokine produced by activated APCs, plays a non-redundant role in regulating Treg cell function. IL-27 acts on the IL-27 specific receptors (made of IL-27Ra and gp130 subunit) expressed on multiple cell types, primarily lymphocytes. Using various genetic approaches, our research focuses on identifying key source of IL-27 in autoimmune inflammation in the central nervous system and underlying mechanism by which IL-27 controls Treg cell function.

2. Glucocorticoids, miR-342, and Treg cells: We recently reported a novel role of Treg cells during glucocorticoid-induced treatment of chronic inflammation. In this study, we discovered a novel micro-RNA-342 molecule that is induced by steroid treatment in Treg cells and directly controls Treg cell metabolism. We are investigating the underlying mechanism by which this new micro-RNA-342 controls Treg cell function.

3. Lag3 and Treg cells: Lag3 is a new immune checkpoint molecule implicated in negatively regulating T cell functions. We discovered that Lag3 is induced by IL-27 stimulation in Treg cells and that Lag3 expression in Treg cells is critical for their suppressive function. We have generated several new mouse models in which Lag3 function and signaling pathways are targeted in a cell type specific manner. These novel animal models will allow us to dissect underlying mechanism of Lag3 in Treg cells and to identify potential therapeutic strategies not only to inhibit inflammation but also to enhance anti-tumor immunity by targeting Lag3 in Treg cells.

For lab information and more, see Dr. Min’s faculty profile and laboratory website.

Publications

See Dr. Min's publications.

Contact

Contact Dr. Min at 312-503-1805.

Lab Staff

Postdoctoral Fellows

Supinya Iamsawat, Dongkyun Kim

Technical Staff

Sohee Kim

 Jason Miska Lab

Studying the metabolism of immune cells in brain tumors 

Research Description

The goal of the Miska laboratory's is to determine how the metabolism of immune cells within brain tumors contributes to immune suppression and tumor recurrence. Furthermore, we seek to manipulate these metabolic pathways in a clinically relevant manner to improve patient outcomes for this deadly disease. Currently, we are exploring how the unique metabolism of tumor-associated myeloid cells (TAMCs) promote their survival, immunosuppression, and tumor brain progression. We have discovered that inhibiting the downstream products of arginine metabolism is a useful strategy for promoting anti-tumor immune responses. Our laboratory also performs immunological monitoring for clinical trials in brain tumor patients by monitoring immune phenotypes, T-cell reactivity, and changes in systemic cytokines that occur with therapeutic administration.

For lab information and more, see Dr. Miska’s faculty profile

Publications

See Dr. Miska's publications.

Contact

Contact Dr. Miska 

 

 Brian Mitchell Lab

Our goal is to understand the integration of signaling and cytoskeletal dynamics on diverse developmental processes including centriole amplification, cell migration and cell polarity.

Research Description

Centrioles are microtubule based structures with nine fold symmetry that are involved in both centrosome organization and aster formation during cell division. During the normal cell cycle centrioles duplicate once, generating a mother/daughter pair and in most post-mitotic vertebrate cells the mother centriole then goes on to form the basal body of a sensory cilium. Abnormalities in the duplication of centrioles (and centrosomes) are prevalent in many cancers suggesting a link between centriole duplication and cancer progression. We study what factors limit centriole duplication from a novel direction with the use of Xenopus motile ciliated cells. Ciliated cells are unique among vertebrate cells in that they generate hundreds of centrioles (basal bodies) therefore providing a great system for studying the regulation of centriole duplication. Understanding how nature has overcome the typically tight regulation of centriole duplication will lend insight into the molecular mechanisms of cancer progression.

Tissue development and homeostasis requires dramatic remodeling as new cells migrate into an epithelium.  How migrating cells breakdown junctional barriers during development or during diseases processes such as metastasis is poorly understood at the molecular level.  During the early development of Xenopus embryos, distinct cell types join the outer epithelium in a process called radial intercalation.  We are interested in the molecular mechanisms that regulate both the migration of these cells as well as the tissue remodeling that occurs to accommodate them. 

The ability of ciliated epithelia to generate directed fluid flow is an important aspect of diverse developmental and physiological processes including proper respiratory function. To achieve directed flow, ciliated cells must generate 100-200 cilia that are polarized along a common axis both within and between cells. My lab is currently working towards understanding the molecular mechanisms for how cell polarity is coordinated as well as how individual cilia interpret the cells polarity. We have determined that ciliated cells receive polarity cues via the non-canonical Wnt/Planar Cell Polarity (PCP) pathway, but the details of this are still poorly understood. Additionally, the PCP pathway is known to influence a cells cytoskeleton dynamics and a main goal is to understand how this influences the ability of individual cilia to coordinate their polarity.

 

For lab information and more, see Dr. Mitchell's faculty profile and lab website.

Publications

See Dr. Mitchell's publications on PubMed.

Contact

Contact Dr. Mitchell at 312-503-9251.

Lab Staff

Postdoctoral Fellows

Caitlin Collins, Jennifer Mitchell, Rosa Ventrella

Technical Staff

Eva Brotslaw, Sun Kim, Ahmed Majekodunmi

 Hidayatullah G. Munshi Lab

The Munshi lab is interested in the role of fibro-inflammatory stromal reaction in pancreatic cancer progression.

The Munshi Lab is focused on understanding the role of the key collagenase MT1-MMP (MMP-14) and members of the Snail family transcription factors in pancreatic cancer progression using transgenic mouse models. We are also interested in understanding how the pronounced fibrotic reaction induces epigenetic changes to contribute to chemotherapy resistance. We have shown that the collagen microenvironment induces histone acetylation and that targeting 'readers' of histone acetylation marks using BET inhibitors can limit growth of pancreatic cancer cells. We plan to evaluate the efficacy of BET inhibitors in our mouse models with the eventual goal of testing this class of inhibitors in patients with pancreatic cancer.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Hidayatullah G Munshi, MD.

Contact Us

Contact Dr. Munshi at 312-695-6180 or the Munshi Lab at 312-503-0312.

Lab Staff

Christina Chow
Post Doctoral Fellow
312-503-0312

Holly Hattaway
Research Technician
312-503-0312

Krishan Kumar
Senior Research Associate
312-503-0312

 Marcus Peter Lab

The lab of Dr. Marcus E. Peter studies various forms of cell death including apoptosis, which is a fundamental process to regulate homeostasis of all tissues and to eliminate unwanted cells specifically in the immune system.

Another interest lies in the study of RNA interference and based on toxic RNAs to development a novel form of cancer treatment. 

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Marcus Peter, PhD or the laboratory's website.

Contact Us

Contact Dr. Peter at 312-503-1291 or the Peter Lab at 312-503-2883.

Lab Staff

Quan Gao
Postdoctoral Fellow

Monal Patel
Postdoctoral Fellow

Qadir Syed
Postdoctoral Fellow

Ashley Haluck-Kangas
Graduate Student

Will Putzbach
Graduate Student

Bryan Bridgeman
Research Technician

Calvin Law
Research Technician

Andrea Murmann
Research Assistant Professor 

 Leonidas Platanias Lab

Dr. Platanias’ research laboratory focuses on understanding the signaling pathways in different types of cancers in order to develop novel therapies to specifically kill cancer cells.

Research Description

Cell signaling is part of an intricate system of events activated by various stimuli that coordinate cell responses. Our laboratory is interested in unveiling pathways involved in cancer development in order to target them and control cancer progression. For over two decades, Dr. Platanias’ laboratory has identified several cellular cascades activated by IFN, ATRA and arsenic. Our research on Type I IFN found an essential role for SKAR protein in the regulation of mRNA translation of IFN-sensitive genes and induction of IFN-α biological responses. We also provided evidence for unique function of mTORC2 complex in inducing Type I IFN response. Our studies on arsenic signaling revealed a direct binding of this compound to a kinase called AMPK as a mechanism underlying its anti-leukemic activity. Other work included the activation of biological responses by BCR-ABL oncoprotein through the mTOR pathway. Dr. Platanias’ laboratory is also involved in testing new compounds in combination with approved therapies in order to identify synergy and improve the risk/benefit ratios of current therapeutic regimens for patients.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Leonidas Platanias, MD, PhD.

Contact Us

Contact Dr. Platanias at 312-908-5250 or the Platanias Lab at 312-503-4500.

Lab Staff

Elspeth Beauchamp, PhD
Research Assistant Professor
312-503-4500

Frank Eckerdt
Research Assistant Professor
312-503-0292

Diana Saleiro
Research Assistant Professor
312-503-4500

Mariafausta Fischietti
Research Assistant Professor
312-503-4283

Ricardo Perez
Postdoctoral Fellow
312-503-4275

Candice Mazewski
Postdoctoral Fellow
312-503-4275

Dominik Nahotko
Graduate Student
312-503-4275

Jamie Guillen
Graduate Student
312-503-4275

Sarah Fenton
PSTP MD Fellow
312-503-4275

Sara Small
PSTP MD Fellow
312-503-4275

Liliana Ilut
Research Technologist 2
312-503-4500

Aneta Baran
Lab Manager/Senior Researcher
312-503-4275

 Paul Schumacker Lab

Oxygen sensing in embryonic development, tissue responses to hypoxia and tumor angiogenesis.

Research Description

Our lab is interested in the molecular mechanisms of oxygen sensing and the importance of this process for embryonic development, tissue responses to hypoxia and tumor angiogenesis. We are testing the hypothesis that the mitochondria play a central role in detecting cellular oxygenation and signal the onset of hypoxia by releasing reactive oxygen species (ROS). These signals trigger downstream signal transduction pathways responsible for the transcriptional and post-translational responses of the cell. Transcriptional activation of genes by Hypoxia-Inducible Factor-1 confers protection against more severe hypoxia by augmenting the expression of glycolytic enzymes, membrane glucose transporters and other genes that tend to augment tissue oxygen supply by increasing the release of vascular growth factors such as VEGF, erythropoietin and vasoactive molecules that augment local blood flow. Current experiments are aimed at improving our understanding of how oxygen interacts with the mitochondrial electron transport chain to amplify ROS production and clarifying the targets that they act on to stabilize HIF and activate transcription.

In specific tissues, oxygen sensing is essential for normal function, but it can also contribute to disease pathogenesis.  For example, during mammalian development, the lung tissue is hypoxic and blood flow is restricted in the pulmonary circulation in order to prevent escape of oxygen from the pulmonary capillaries to amniotic fluid.  At birth, inflation of the lung with air causes an increase in lung oxygen levels, which triggers relaxation of pulmonary arteries.  In Persistent Pulmonary Hypertension of the Newborn, failure of the pulmonary circulation to dilate results in elevated pulmonary arterial pressures and significant lung gas exchange dysfunction.  We are testing the hypothesis that pulmonary vascular cells sense O2 at the mitochondria and that ROS released from those organelles trigger an increase in cytosolic calcium, which causes smooth muscle cell contraction.  In adult patients with hypoxic lung disease, similar activation of hypoxic vasoconstriction can lead to chronic pulmonary hypertension, which can progress to right heart failure.  A fuller understanding of the mechanisms of oxygen sensing in health and disease may lead to insights into therapeutic inhibition of this response in disease states.

In solid tumors, consumption of oxygen by highly metabolic tumor cells leads to hypoxia and threatens glucose supplies.  Hypoxic tumor cells retain their oxygen sensing capacity and turn on expression of HIF-dependent genes, leading to tumor angiogenesis and increased blood supply, which permits further growth.  We are currently exploring the hypothesis that the mitochondrial oxygen sensor is required for this response using pursuing genetic models.  A better understanding of how tumor cells detect hypoxia could lead to the discovery of therapeutic approaches that would prevent detection of hypoxia and thereby prevent tumor progression.

For more information visit Dr. Schumacker's faculty profile page

Publications

View Dr. Schumacker's publications at PubMed

Contact

Email Dr. Schumacker

Phone 312-503-1476

 Alexander Stegh Lab

Dr. Stegh’s lab aims to define and target the oncogenome of glioblastoma.

Research Description

Our research program is aimed at understanding the genetic program that underlies the pathogenesis of Glioblastoma multiforme (GBM), the most prevalent and malignant form of brain cancer. Applying a combination of cell/molecular biology, oncogenomic and mouse engineering approaches, we are dedicated to systematically characterize novel gliomagenic oncogenes and tumor suppressors. We will functionally delineate and validate these pathways using cell culture and animal models and develop novel nanotechnological approaches to target these aberrations in established tumors.

For more information see the faculty profile of Alexander H. Stegh MD, PhD, or visit the Alexander H. Stegh Lab website.

Recent Publications

View Dr. Stegh's full list of publications at PubMed.

Contact

Email Alexander Stegh, MD, PhD 

Phone: 312-503-2879

Twitter: @ahstegh

 Marie-Pier Tetreault Lab

The Tetreault Lab uses novel mouse models and three-dimensional organotypic culture to delineate the reciprocal contributions of the epithelium and the microenvironment to inflammatory diseases of the gastrointestinal tract. 

Our research program focuses on diseases of the esophagus, which are among the most common ailments in the United States and throughout the world, resulting in significant morbidity, mortality and healthcare expenditures. Understanding the molecular mechanisms underlying esophageal disease pathogenesis is crucial and will lead to considerable improvements in the diagnosis and the treatment of esophageal diseases. Although alterations of the microenvironment have been described in esophageal diseases, such as esophageal cancer and esophagitis, our knowledge of the molecular mechanisms that mediate changes in the microenvironment and that regulate epithelial-stromal interactions in the context of esophageal diseases is still very limited.

Our research program focuses on two key inflammatory pathways: the IKKβ/NFκB and STAT3 pathways. We employ novel in vitro and in vivo models and state-of-the-art methodology to define key factors regulating epithelial-epithelial and epithelial-stromal signaling in the esophagus. More specifically, our goal is to better understand:

  1. How epithelial IKKb regulates the balance between angiogenic and angiostatic factors and how it affects the stromal microvasculature
  2. How epithelial IKKb contributes to the phenotypic heterogeneity of stromal fibroblasts
  3. How epithelial IKKb controls the recruitment of immune cells
  4. The complex interplay existing between IKKb and STAT3 signaling pathways

We expect that these investigations will uncover novel diagnostic and therapeutic targets for esophageal diseases.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Marie-Pier Tetreault, PhD.

Contact Us

Email Dr. Tetreault

Contact the Tetreault Lab at 312-503-1915

 Jacek Topczewski Lab

Morphogenetic processes in vertebrate embryo

Research Description

Animal development requires proper specification of different cell types and, at the same time, their organization in to multicellular arrangements such as tissues and organs. My laboratory investigates the mechanisms that control morphogenetic processes in vertebrate embryo. We are studying these processes in the zebrafish (Danio rerio) using a combination of genetic analysis with embryological and molecular methods. The transparency of zebrafish embryos together with the generation of fluorescent transgenic animals allows us to use high-resolution confocal microscopy for in vivo analysis of cell behaviors. Moreover, similarities in developmental programs among all vertebrates make zebrafish an excellent model for investigating human diseases and development.

We are focusing current efforts on the mechanisms that shape the zebrafish head skeleton. We are particularly interested in the role of non-canonical Wnt signaling in cartilage morphogenesis. Mutants with altered non-canonical Wnt signaling pathways exhibit similar cell behavior defects during gastrulation and cartilage morphogenesis. This observation led to the hypothesis that non-canonical Wnt signaling controls cartilage element morphology by modification of chondrocyte behavior. My work on the characterization of the zebrafish knypek gene has revealed a new role for glypicans (heparan sulfate proteoglycan) in controlling morphogenetic movements during gastrulation by promoting non-canonical Wnt11 signaling. We are investigating the function of non-canonical Wnts and their potential co-receptors, glypicans, in chondrocyte differentiation and polarization. Because the initial steps in craniofacial development are similar in all vertebrates, these studies will help understand genetic basis for relatively frequent congenital anomalies causing abnormal development of the hard and soft tissue of the head and neck.

We are also interested in the developmental roles of other glypicans, as these extracellular proteins can play an essential role by interaction with growth factors, chemokines, extracellular matrix proteins, enzymes and enzyme inhibitors. Glypicans can be involved in regulation of ligand-receptor interactions and control of ligand distribution, both within a tissue and on the cell surface. For example, the clinical features of Simpson-Golabi-Behmel overgrowth syndrome, caused by mutation in the gene encoding Glypican 3, suggest that this protein is involved in regulation of cell survival and/or proliferation. One goal of my laboratory is to identify zebrafish glypicans and characterize developmental processes that they are regulating.

For more information view Dr. Topczewski's faculty profile page

Publications

View Dr. Topczewski's publications at PubMed

Contact

Email Dr. Topczewski

Phone 773-755-6545

Lab Staff

Graduate Students

Rebecca Anderson

 Derek Wainwright Lab

Studying malignant glioma, with a special emphasis on glioblastoma; pursuing incurable pediatric brain tumors and metastatic tumors that invade the brain/spinal cord.

Research Description

Our laboratory utilizes DNA sequencing, gene expression profiling, proteomic analyses, flow cytometric methodology and many other basic techniques to pursue goals that are ultimately translatable for improving health and overall survival in patients with brain cancer. Although our research is primarily focused on malignant glioma, with a special emphasis on glioblastoma, we are also interested in pursuing incurable pediatric brain tumors, as well as metastatic tumors that invade the brain/spinal cord. It is our sincere hope that the basic mechanistic investigations that we carry out will uncover important and meaningful discoveries that translate into highly effective immunotherapeutic modalities for the benefit of patients with incurable cancer in the brain. 

For more information, please see Derek Wainwright's, PhD, faculty profile or lab website.

Publications

Please see Dr. Wainwright's publications in PubMed.

Contact Wainwright Lab

Contact the Wainwright Lab at 312-503-3161 or visit us on campus in Tarry 2-703.

 Yong Wan Lab

Defining the molecular mechanisms of breast tumor initiation, progression, and metastasis, and identifying novel targets for therapeutic development.

Research Description

The overarching goal of Wan laboratory is to define the molecular mechanisms of breast tumor initiation, progression, and metastasis, and to identify novel targets for therapeutic development. Particularly, the laboratory seeks to address how defects in the ubiquitin-proteasome system and other posttranslational modifiers such as protein methyltransferase, poly (ADP-ribose) polymerase and glycosyltransferase would result in genomic instability, deregulated tumor immune checkpoint function, abnormal cell cycle, and aberrant signaling that predispose otherwise normal cells to become cancerous tumor cells or promote cancer progression and metastasis. The research approaches in Wan laboratory include biochemical, cell biological, genetic, protein structural analyses as well as the use of breast cancer animal models and analyses of clinical specimens.

For lab information and more, see Dr. Wan's faculty profile.

Recent Findings

  • Pharmacological suppression of B7-H4 glycosylation restores antitumor immunity in immune-cold breast cancers.2020. Cancer Discovery (in press)
  • EIF3H Orchestrates Hippo Pathway-Mediated Oncogenesis via Catalytic Control of YAP Stability.  PMID: 32269044
  • A novel strategy to block mitotic progression for targeted therapy. PMID: 31669221
  • A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy. PMID: 31101597

Current Projects

Publications

See Dr. Wan's publications on PubMed.

Contact

Contact Dr. Wan at 312-503-2769.

Lab Staff

Research Assistant Professor:

Yueming Zhu

Postdoctoral Fellows:

Cindy Mandy Wavelet
Olena Odnokoz

Graduate students:

Jack Chi
Shelby Hophan
Valentina Medvedeva

 Dileep Varma Lab

Chromosome segregation, genomic instability and cancer biogenesis

Research Description

The broad area of our research interest is in the cytoskeleton and intracellular motility. The cytoskeletal polymer that we are most interested in is the microtubules and the cytoskeletal process that we are most excited about is the accurate segregation of chromosomes during mitosis. A dividing cell assembles mitotic kinetochores and a mitotic spindle at the onset of mitosis. The kinetochores serve as sites where the microtubules of the mitotic spindle comes in physical contact with the chromosomes and are hence extremely important for accurate chromosome segregation. Improper kinetochore microtubule (kMT) attachments lead to erroneous chromosome segregation, chromosome loss and aneuploidy in turn, which is the leading cause of cancer in tissue cells and of birth defects and miscarriages during human embryonic development.

Over a decade of research had identified the kinetochore-bound Ndc80 complex as the key requirement for the direct physical contact with microtubules of the spindle. But what is still not understood well is how the kinetochores and the Ndc80 complex remains stably attached to the highly dynamic microtubule plus-ends during mitotic metaphase and subsequent chromosome segregation in anaphase. Work is yeast model system had provided us with important insights into the possible mechanism governing this process, but we still do not have a clear mechanistic picture in vertebrate systems. Work in our lab focusses on understanding the molecular mechanisms that are involved the controlling and regulating kinetochore microtubule attachments in vertebrate cells. We are also very interested to delineate the intricate mechanism that link this event with the activation and silencing of the spindle assembly checkpoint which is also absolutely critical for accurate chromosome segregation

For lab information and more, see Dr. Varma's faculty profile and lab website.

Publications

See Dr. Varma's publications on PubMed.

Contact

Contact Dr. Varma at 312-503-4318 or the lab at 312-503-0824.

Lab Staff

Postdoctoral Fellows

Shivangi Agarwal, Mohammed Amin, Amit Rahi

Graduate Student

Adriana Landeros

 Bin Zhang Lab

The Zhang Lab investigates the tumor-induced immune suppression.

Dr. Zhang’s laboratory work is focused on understanding the mechanisms of tumor-induced immune evasion. The overall goal is to develop novel and feasible strategies to improve cancer immunotherapy. He has been recently interested in the tumor microenvironment complexity whereby CD73 functions as an ecto-enzyme to produce extracellular adenosine, which limits anti-tumor T cell immunity. He is exploring the detailed mechanisms of CD73 by which the tumors evade the immune system using a combination of molecular, biochemical and mouse genetic approaches and to accomplish the targeted elimination of CD73 as a novel means to enhance cancer immunotherapy. Other ongoing studies involve: (1) Analyze the contribution of new key molecules including microRNAs from the perspective of cancer immunology in regulating regulatory T cells and/or myeloid derived suppressive cells;  (2) Define a novel use of pre-existing chemotherapy drugs to overcome tumor-mediated immunosuppression; (3) Characterize the role of novel molecules in tumor T cell immunity and autoimmunity; (4) Understand the differential immune regulation in GVHD vs. GVL; and (5) Develop new animal models that can be employed in preclinical studies to most reflect human clinical trials.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Bin Zhang, MD/PhD.

Contact Us

Contact Dr. Zhang at 312-695-6180 or the Zhang Lab at 312-503-2435.

Lab Staff

Siqi Chen
Graduate Student
312-503-2435

Donye Senon Dominguez
Graduate Student
312-503-2432

Jie Fan
Senior Technician
312-503-2435 

Alan Long
Grad student
312-503-2432

Lei Qin
Postdoc Scholar
312-503-2432

 Ming Zhang Lab

Molecular Mechanisms of Tumorigenesis and Cancer Metastasis

Research Description

The Zhang laboratory is focused on two research directions: 1) determining role of tumor suppressors in development and cancer progression and 2) identifying immune components that control breast cancer metastasis.

The main focus of my research program is to study the roles of tumor suppressors in normal development and in breast and prostate cancer progression, focusing on maspin and an Ets transcription factor PDEF. Maspin is a unique member of the SERPIN family that plays roles in normal tissue development, tumor metastasis and angiogenesis. Genetic studies by my laboratory using maspin transgenic and knockout mice demonstrated an important role of maspin in normal mammary, prostate and embryonic development. Recently, we have identified several new properties of maspin. As a protein that is present on cell surface, maspin controls cell-ECM adhesion. This function is responsible for maspin-mediated suppression of tumor cell motility and invasion. We have also discovered that maspin is involved in the induction of tumor cell apoptosis through a mitochondrial death pathway. The long-term goals of these projects are to elucidate the molecular mechanisms by which maspin and PDEF control tumor metastasis and to identify their physiological functions in development. These analyses are not only important for basic biology and but also may lead to a therapy for cancer and other developmental diseases.

Another focus of research in Zhang lab is to identify immune components that control breast cancer metastasis. Chronic inflammation not only increases neoplastic transformation but also drives the inhibition of the immune response in a protective negative-feedback mechanism.  Suppressive immune cells are recruited to the sites of inflammation and function to inhibit both innate and adaptive immune responses, enabling tumor tolerance and unmitigated tumor progression. To study the interplay between tumor and immune cells, the Zhang lab has developed a unique animal model of breast cancer that reproduces different stages of breast cancer bone metastasis. Molecules that control tumor-immune cell interaction and immunosuppression have been identified. We are currently studying roles of these genes in tumor-driven evolution that control chronic inflammation and immunosuppression. We hypothesize that these key pro-inflammatory genes are upregulated during cancer progression, which function synergistically to recruit and activate suppressive MDSCs, TAMs and Tregs, inducing chronic inflammation and an immunosuppressive tumor microenvironment conducive to metastatic progression.

For more information visit Ming Zhang's faculty profile.

Publications

View publications by Ming Zhang in PubMed

Contact

Dr. Zhang

Phone 312-503-0449

 Zhuoli Zhang Lab

The Zhang Lab investigates molecular/cellular MR imaging and functional imaging guided immunotherapy.

Dendritic cells (DCs) are the most potent antigen-presenting cells and tumor antigen-loaded DCs (DC-vaccines) can activate tumor-specific cytotoxic T lymphocytes in lymphatic tissues. DC vaccine immunotherapy has demonstrated great potential for the systemic treatment of cancers, but the clinical outcomes of DC-vaccine studies have been extremely variable. We will pay attention to DC-based vaccination induced tumor apoptosis and how that can affect treatment outcomes. The efficacy of DC-vaccines is strongly influenced by their ability to migrate to the draining lymph nodes (LNs). Therefore, visualization of in vivo DC-vaccine migration to the draining LNs should help predict therapeutic response. We propose that magnetic labeling of DC-vaccines will permit magnetic resonance imaging (MRI) of biodistribution. We will develop and optimize quantitative MRI-guided DC vaccination for PDAC therapy. This project will be carried out in a well-established transgenic KPC mouse model of PDAC (LSL-KrasG12D-LSLTrp53R172H-Pdx-1-Cre) that mimics both the genetic and histologic changes observed in human pancreatic cancer.

Publications

View lab publications via PubMed.

For more information, visit the faculty profile page of Zhuoli Zhang, MD/PhD.

Contact Us

Email Dr. Zhang

Phone Dr. Zhang at (312) 926-3874

 Youyang Zhao Lab

The Zhao Lab studies the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury as well as endothelial and smooth muscle cell interaction in the pathogenesis of pulmonary vascular diseases.

Research Description

Recovery of endothelial barrier integrity after vascular injury is vital for endothelial homeostasis and resolution of inflammation. Endothelial dysfunction plays a critical role in the initiation and progression of vascular diseases such as acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and atherosclerosis. A part of the research in the lab, employing genetically modified mouse models of human diseases, endothelial progenitor cells/stem cells, and translational research approach as well as nanomedicine, is to elucidate the molecular mechanisms of endothelial regeneration and resolution of inflammatory injury and determine how aging and epigenetics regulate these processes (J. Clin. Invest. 2006, 116: 2333; J. Exp. Med. 2010, 207:1675; Circulation 2016, 133: 2447).  We are also studying the role of endothelial cells in regulating macrophage functional polarization and resolving inflammatory lung injury. These studies will identify druggable targets leading to novel therapeutic strategies to activate the intrinsic endothelial regeneration program to restore endothelial barrier integrity and reverse edema formation for the prevention and treatment of ARDS in patients.

Pulmonary hypertension is a progressive disease with poor prognosis and high mortality. We are currently investigating the molecular basis underlying the pathogenesis.  We have recently identified the first mouse model of pulmonary arterial hypertension (PAH) with obliterative vascular remodeling including vascular occlusion and formation of plexiform-like lesions resembling the pathology of clinical PAH (Circulation 2016, 133: 2447). Our previous studies also show the critical role of oxidative/nitrative stress in the pathogenesis of PAH as seen in patients (PNAS 2002, 99:11375; J. Clin. Invest. 2009, 119: 2009). With these unique models and lung tissue and cells from idiopathic PAH patients, we will define the molecular and cellular mechanisms underlying severe vascular remodeling and provide novel therapeutic approaches for this devastating disease. 

The Zhao lab employs the state-of-the art technologies including genetic lineage tracing, genetic depletion, genetic reporter, and CRISPR-mediated in vivo genomic editing as well as patient samples to study the molecular mechanisms of acute lung injury/ARDS, and pulmonary hypertension and identify novel therapeutics for these devastating diseases. Current studies include 1) molecular mechanisms of endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis and pneumonia; 2) how aging and epigenetics regulate this process; 3) how endothelial cells regulate macrophage and neuptrophil function for resolution of inflammation and host defense; 4) stem/progenitor cells in acute lung injury and pulmonary hypertension and cell-based therapy; 5) mechanisms of obliterative pulmonary vascular remodeling; 6) molecular basis of right heart failure; 7) pathogenic role of oxidative/nitrative stress; 8) lung regeneration; 9) drug discovery; 10) nanomedicine.


Publications

View publications by Youyang Zhao in PubMed.

For more information, visit Dr. Zhao's Faculty Profile page

Contact

Email Dr. Zhao

Contact Dr. Zhao’s Lab at 773-755-6355

Lab Staff

Zhiyu Dai, PhD.
Research Assistant Professor

Xianming Zhang, PhD.
Research Assistant Professor

Narsa Machireddy, PhD.
Research Assistant Professor

Junjie Xing, PhD.
Research Scientist

Colin Evans, PhD.
Research Scientist

Varsha Suresh Kumar, PhD.
Research Scientist

Xiaojia Huang, PhD
Research Scientist

Hua Jin, PhD
Postdoctoral fellow

Yi Peng, PhD
Research Scientist

Mengqi Zhu, M.S.,
Graduate Student

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