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Cell Adhesion and Metastasis

Research into the basic mechanisms of cell adhesion and motility in cancer, with particular emphasis on the process of metastasis.

Labs in This Area

 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.

 

 Robert Goldman Lab

Studying the intermediate filament (IF) system in fibroblasts, epithelial cells and nerve cells through biochemical, morphological, immunological, cell physiological and molecular techniques.

Research Description

We focus on the structure and function of cytoskeletal systems, particularly the intermediate filament (IF) system in fibroblasts, epithelial cells and nerve cells. IFs are composed of large families of proteins that vary in composition from one cell type to another, even among cells in the same tissue. Using a variety of techniques, we have demonstrated that IFs form elaborate networks that course throughout the cytoplasm and establish connections with both the nuclear and cell surfaces.

At the nuclear surface, they are linked either directly or indirectly with the nuclear lamins, which are chromatin-associated IF protein family members. At the level of the plasma membrane, IFs are involved as cytoskeletal linkages to the focal adhesion of fibroblasts and the desmosomes and hemidesmosomes of epithelial cells. Throughout the cytoplasm, we have shown that IFs are associated with the other cytoskeletal elements, such as microtubules and microfilaments.

Our approach to studying the IF system involves biochemical, morphological, immunological, cell physiological and molecular techniques. Our hypothesis is that the IF system forms a continuous network linking the nuclear and cell surfaces, functioning in such diverse activities as the establishment and maintenance of cell shape, organelle movements within the cytoplasm, nuclear positioning, nuclear-cytoplasmic interactions and signal transduction.

Since many human diseases have been linked to changes in cytoskeletal IF systems, we are also developing models to study the mechanisms involved in IF alterations in various diseases. One example is amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) in which we have been able to induce neurofibrillary tangles to form in single cultured nerve cells. These tangles are similar to those found in ALS neurons. Therefore, we are able to study the effects of neurofilament tangle formation in single cells. During the summer, researchers from this laboratory also conduct studies on the mechanisms of chromatin/nuclear envelope interactions in eggs of the surf clam at the Marine Biological Laboratory in Woods Hole.

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

Publications

See Dr. Goldman's publications on PubMed.

Contact

Contact Dr. Goldman at 312-503-4215.

Lab Staff

Research Faculty

Heike Folsch, Edward Kuczmarski, Stuart Stock

Postdoctoral Fellows

Anne Goldman, Mark Kittisopikul, Suganya Sivagurunathan, Amir Vahabikashi

Technical Staff

Kyung Myung, Fiona Nicdao, Samuel Romo

 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

 

 Kathleen Green Lab

Cell-to-cell adhesion molecules' integration of mechanical and signaling functions in skin and heart differentiation, disease and cancer.

Research Description

Dr. Green's research program focuses on how cell-cell adhesion molecules and their associated proteins integrate mechanical and chemical signaling pathways to contribute to the development and maintenance of multicellular tissues. In particular they are investigating how specialized intercellular junctions called desmosomes are assembled and function in ways that transcend their classic textbook definition as spot welds. The lab has shown that desmosomal cadherins help control the balance of proliferation and differentiation and even regulate the production of cytokines that participate in paracrine signaling. Loss of this “brake” results in increased allergic and inflammatory pathways that underlie pathogenesis in inherited disease and possibly cancer, including melanoma. Desmosomes also integrate the functions of other intercellular junctions including gap junctions and interfering mutations can cause lethal heart arrhythmias.

The lab uses a multi-faceted approach, including but not limited to collaborative atomic structure determinations, molecular genetics, live cell imaging, human tissue engineering and gene targeting approaches. Dr. Green serves as Associate Director for Basic Sciences in the R.H. Lurie Comprehensive Cancer Center.

For more information, please visit the Green Lab website and the faculty profile of Kathleen J Green, PhD.

Publications

See Dr. Green's publications in PubMed.

Contact

Dr. Green

 Luisa Iruela-Arispe Lab

Molecular regulation of angiogenesis and vascular homeostasis

Research Description

Currently, the laboratory is investigating the mechanisms behind the formation of vascular tumors and vascular anomalies. In particular, the group is interested in the identification of critical regulatory nodes that maintain vascular homeostasis and control endothelial proliferation in the context of flow. An additional focus of the lab is to dissect the molecular interactions between endothelial and tumor cells during the process of metastasis with particular emphasis on endothelial barrier.

For lab information and more, see Dr. Iruela-Arispe's faculty profile.

Publications

See Dr. Iruela-Arispe's publications on PubMed.

Contact

Email Dr. Iruela-Arispe

 

 

 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

 William Muller Lab

Focusing on the emigration of leukocytes across vascular endothelial cells in the process of inflammation

Research Description

Most diseases are due to or involve a significant component of inflammation. My lab studies the inflammatory response at the cellular and molecular level. We are focused on the process of diapedesis, the "point of no return" in inflammation where leukocytes squeeze between tightly apposed endothelial cells to enter the site of inflammation. We have identified and cloned several molecules that are critical to the process of diapedesis (PECAM (CD31), CD99, and VE-cadherin) and are studying how they regulate the inflammatory response using in vitro and in vivo models. We have recently described the Lateral Border Recycling Compartment, a novel para-junctional organelle that contains PECAM and CD99 and is critical for diapedesis to occur. We are currently investigating how this compartment regulates diapedesis in the hope of finding novel and highly specific targets for anti-inflammatory therapy.

The “holy grail” of therapy is to develop selective anti-inflammatory agents that block pathologic inflammation without interfering with the body’s ability to fight off infections or heal wounds.  By understanding how endothelial cells at the site of inflammation regulate leukocyte diapedesis, we are hoping to do just that.  We have identified several molecules critical for diapedesis in acute and chronic inflammatory settings that can be genetically deleted or actively blocked to markedly inhibit clinical symptoms (e.g. in a mouse model of multiple sclerosis) and tissue damage (e.g. in a mouse model of myocardial infarction) without impairing the normal growth, development, and health of these mice.  Our inflammatory models include atherosclerosis, myocardial infarction, ischemia/reperfusion injury, stroke, dermatitis, multiple sclerosis, peritonitis, and rheumatoid arthritis. We are also using 4-dimensional intravital microscopy to view the inflammatory response in real time in living animals.

Basic questions/issues that the work seeks to address:
  • What are the molecular mechanisms and signaling pathways that endothelial cells use to regulate the inflammatory response?
  • How can we therapeutically treat inflammatory diseases without compromising the ability of the immune system to respond to new threats?
  • Do circulating tumor cells use the same mechanisms as leukocytes to cross blood vessels when they metastasize?

Our Facilities

We have a high-resolution Perkin Elmer ULTRAVIEW Vox System spinning disk laser confocal microscope in the upright configuration on an Olympus BX51WI fixed stage in my laboratory designed for intravital microscopy.  We can image the ongoing inflammatory response and response to our drugs in real time in anesthetized mice with unprecedented temporal and spatial resolutions.  We presently image inflammation in the cremaster muscle, intestine, and brain.

Of interest to History of Science buffs, we have the original Zeiss Ultrafot II microscope used to film the first movies of neutrophils ingesting bacteria. As you might expect from something built by Zeiss in the first half of the 20th century, the optics are still fantastic and we use it in our daily work.

Our Successes

Recently we made two major discoveries in endothelial cell inflammatory signaling: Identification of TRPC6 as the cation channel responsible for the endothelial cell calcium flux required for transmigration and description of the CD99 signaling pathway.  Both had eluded discovery for decades.

  • Watson, R.L., J. Buck, L.R. Levin, R.C. Winger, J. Wang, H. Arase, and W.A. Muller. 2015. Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte   transendothelial migration. J. Exp. Med. 212:1021-1041.
  • Weber, E.W., F. Han, M. Tauseef, L. Birnbaumer, D. Mehta, and W.A. Muller. 2015. TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-1899. PMID:    26392222

Recent Awards

  • AAAS Fellow, elected 2010
  • Rous-Whipple Award, American Society for Investigative Pathology, 2013
  • Ramzi Cotran Memorial Lecture, Brigham and Women’s Hospital, 2014
  • Karl Landsteiner Lecture, Sanquin Research Center, Amsterdam, Netherlands, 2016
  • Member, Faculty of 1000 Leukocyte Development Section
  • American Society for Investigative Pathology (ASIP) Council
  • ASIP Research and Science Policy Committee Chair
  • North American Vascular Biology Organization (NAVBO) Secretary-Treasurer

Grants Won

  • NIH R01 HL046849-26 William A. Muller                     08/01/91 – 05/31/20

    The Roles of Endothelial PECAM and the LBRC in Leukocyte Transmigration

    This study investigates how PECAM-1 and the LBRC regulate transmigration.  We will investigate how PECAM ligation on endothelial cells activates TRPC6 to promote the calcium flux necessary for transmigration (Aim I).  We will identify how endothelial IQGAP1 regulates transmigration by regulating targeted recycling of the LBRC (Aim II).  We will identify how kinesin light chain 1 variant 1 facilitates movement of the LBRC during targeted recycling (Aim III).  All of these Aims include mechanistic studies in vitro and validation studies in vivo using mouse models of ischemia/reperfusion injury in acute inflammation and myocardial infarction.

  • NIH R01 HL064774-16 William A. Muller                     04/01/00 – 08/31/20

    Beyond PECAM:  Mechanisms of Transendothelial Migration

    This study investigates the role of PECAM, CD99L2, and CD99 in transendothelial migration.  Aim I will test the hypothesis that leukocytes control the molecular order of transmigration by polarizing PECAM on their leading edge and CD99 on the trailing edge during transmigration.  Aim II will identify the signaling mechanisms by which CD99L2 regulates transmigration.  Aim III will identify the signaling mechanisms by which CD99 regulates targeted recycling of the LBRC and transmigration downstream of Protein Kinase A.  All Aims have in vitro mechanistic studies and in vivo validation studies using intravital microscopy in the cremaster muscle circulation and a murine model of ischemia/reperfusion injury in myocardial infarction.

For more information, visit the faculty profile of William A Muller, MD, PhD

Publications

View Dr. Muller's publications at PubMed

Staff

Research Assistant Professors

Assistant Professor (Department of Neurology) Research Resident (PSTP) Graduate Students Research Associates Technical Staff

Contact

Bill Muller

Office: Ward Building, Room 3-126
303 East Chicago Avenue
Chicago, IL 60611-3008

Phone: (312) 503-0436
Fax: (312) 503-8249
E-mail:  wamuller@northwestern.edu

Lab: Ward Building 3-070 and 3-031
Lab Phone: (312) 503-5200
Lab Fax: (312) 503-2630

 Karen M. Ridge Lab

The Ridge Lab investigates the role of intermediate filaments in lung pathophysiology

The cytoskeletal protein vimentin plays a key role as a scaffold for the formation and activation of intracellular protein complexes. One such complex is the NLRP3 inflammasome, which assembles in response to danger signals such as influenza A virus or ATP released by damaged cells to produce mature IL-1β and IL-18. These inflammatory cytokines can induce lung injury, which can lead to fibrosis. One of our current goals is to pinpoint vimentin’s role in inflammasome assembly and activation.

Vimentin is also involved in all stages of cancer development, from PI3K/AKT and Erk pathway regulation in tumerigenesis, to its defining role in epithelial-to-mesenchymal transition, to metastatic cell invasion and migration, making it an intriguing therapeutic target. Our purpose in examining vimentin’s role in lung cancer is to determine whether its inhibition might be of benefit to patients.

Publications

View our lab’s publications in PubMed.

To learn more, please visit the faculty profile pages of Karen M. Ridge, PhD

Visit the Ridge Lab Website

Contact Us

Email Dr. Ridge
Phone 312-503-1648 or the Ridge Lab at 312-503-0403

Lab Staff

Alexandra Berr
Graduate Student
312-503-0403

Yuan Cheng
Research Technologist 2
312-503-0403

Mark Ciesielski
Research Technologist 1
312-503-0403

Bria Coates, MD
Assistant Professor
312-227-4800

Jennifer Davis
Research Technologist I
312-503-0403

Francisco Gonzalez, MD
Postdoctoral Research Fellow

Grant Hahn, MD
Critical Care Medicine Fellow

Jennifer Yuan-Shih Hu, PhD
Postdoctoral Research Fellow
312-503-4845

Clarissa Masumi Koch, PhD
Postdoctoral Research Fellow
312-503-0403

Dale Shumaker, PhD
Research Assistant Professor
312-503-1918

Margaret Turner
Research Technologist 1
312-503-4845

 Beatriz Sosa-Pineda Lab

The Sosa-Pineda lab studies studies the regulation of acinar cell development and plasticity in the pancreas, hepatic cell fate, and liver zonation. We also investigate mechanisms that promote pancreas metastasis.

Research Description

Using genetically modified mouse models and cutting-edge technologies, we investigate how the complex architecture of the mammalian pancreas and liver is established during development. We also investigate how acute or chronic injury affect liver zonation and exocrine pancreas homeostasis, and the role of chromosomal instability in pancreatic tumor formation and metastasis.

 

For more information, visit the faculty profile of Beatriz Sosa-Pineda, PhD or the Sosa-Pineda lab web site.

Publications

View Dr. Sosa-Pineda's publications at PubMed

Contact

Email Dr. Sosa-Pineda

Phone 312-503-2296

 Ronen Sumagin Lab

Contributions of immune cell-mediated inflammation to development and progression of colorectal cancers

Research Description

Immune cells are critical for host defense, however immune cell infiltration of mucosal surfaces under the conditions of inflammation leads to significant alteration of the tissue homeostasis. This includes restructuring of the extracellular matrix and alterations in cell-to-cell adhesions. Particularly, immune cell-mediated disruption of junctional adhesion complexes, which otherwise regulate epithelial cell polarity, migration, proliferation and differentiation can facilitate both tumorigenesis and cancer metastasis. Our research thus focuses on understanding the mechanisms governing leukocyte induced tissue injury and disruption of epithelial integrity as potential risk factors for tumor formation, growth and tissue dissemination.

For publication information see PubMed and for more information see Dr. Sumagin's faculty profile page or laboratory site.

Contact information

Ronen Sumagin, PhD
Assistant Professor in Pathology
312-503-8144
Email:  ronen.sumagin@northwestern.edu

 Wu Lab

Dr. Wu’s laboratory studies the molecular mechanisms regulating gene expression and their involvement in the pathogenesis of age-related diseases, including neurodegeneration and tumor metastasis.

Research Description

RNA Processing and Neurodegeneration

Accumulating evidence supports that aberrant RNA processing represents a general pathogenic mechanism for neurodegeneration, including dementia and amyotrophic lateral sclerosis (ALS). A number of RNA binding proteins (RBPs) have been associated with neurodegenerative diseases, especially various proteinopathies. Recent studies have defined TDP-43 and FUS proteinopathies, a group of heterogeneous neurodegenerative disorders overlapping with dementia, including frontotemporal lobar degeneration (FTLD) and ALS. Several important questions drive our research: what is physiological function of these RBPs? What are the fundamental mechanisms by which genetic mutations in or aberrant regulation of these RBPs cause neural damage? What are the earliest detectable molecular and cellular events that reflect the neural damage in these devastating neurological diseases? How to reverse/repair the neural damage and slow down the progression of these devastating diseases.

To address these questions, we have established cellular and animal models for both TDP-43 and FUS proteinopathies (Li et al, 2010;Barmada et al, 2010; Chen et al, 2011; Fushimi et al, 2011). Using combined biochemical, biophysical, molecular biology and cell biology approaches, we have begun to examine the molecular pathogenic mechanisms underlying neurotoxicity induced by TDP-43 and FUS. Our recent work using atomic force microscopy (AFM), electron microscopy (EM) and (NMR) approaches has shown the biochemical, biophysical and structural similarities between TDP-43 and classical amyloid proteins (Guo et al, 2011; Xu et al, 2013; Bigio et al, 2013). Our study has defined a minimal amyloidogenic region at the carboxyl terminal domain of TDP-43 that is sufficient for amyloid fibril formation and neurotoxicity (Guo et al, 2011; Zhu et al, unpublished). Using cellular and animal models for FUS proteinopathy, we have begun to identify the earliest detectable cellular damage caused by mutations in and overexpression of the human FUS gene. Our data have provided new insights into pathogenic mechanisms underlying these proteinopathies and suggested candidate targets for developing therapeutic approaches.

A critical step in mammalian gene expression is the removal of introns by the process of pre-mRNA splicing. Alternative pre-mRNA splicing, the process of generating multiple mRNA transcripts from a single genetic locus by alternative selection of distinct splice sites, is one of most powerful mechanisms for genetic diversity and an excellent means for fine-tuning gene activity. Many genes critical for neuronal survival and function undergo extensive alternative splicing. Splicing defects play important roles in neurodegenerative disorders such as dementia and motor neuron diseases. For example, splicing mutations in the human tau gene and imbalance of tau splicing isoforms lead to frontotemporal lobar degeneration with tau-positive pathology (FTLD-tau). To understand mechanisms underlying FTLD-tau, we have set up a model system and developed a number of biochemical, molecular and cell biological assays to study alternative splicing of the human tau gene. Our work has led to the identification of a number of cis-elements and trans-acting RBPs controlling tau alternative splicing (Kar et al, 2006; Wu et al, 2006; Kar et al, 2011; Ray et al, 2011). Our experiments have begun to reveal previously unknown players in FTLD-tau and provided new candidate target genes for developing therapeutic strategy (Donahue et al, 2006; unpublished).

Molecular Mechanisms Regulating Axon Guidance, Cell Migration & Tumor Metastasis

Another line of our research focuses on the cellular and molecular mechanisms regulating cell migration and cancer metastasis. Previous studies from our group and others led to the discovery of Slit as a prototype of neuronal guidance cue. Our studies have shown that Slit interacts with Roundabout (Robo) and acts as a chemorepellent for axons and migrating neurons (Wu et al, 1999; Li et al, 1999;Yuasa-Kawada et al, 2009). Our work has demonstrated that Slit-Robo signaling modulates chemokines and inhibits migration of different types of cells, including cancer cells. The observation that Slit is frequently inactivated in a range of tumors suggests an important role of Slit in tumor suppression. We have established several assays and shown that Slit inhibits invasion and migration of cancer cells, including breast cancer, glioma and prostate cancer. We are using combined molecular and cell biology approaches to dissecting Slit-Robo signaling in neuronal guidance and tumor suppression. Our research has provided new insights into signal transduction pathways mediating Slit function. Enhancing or activating the endogenous mechanisms that restrict or suppress cancer invasion/metastasis will likely provide novel approaches to cancer metastasis. 

For more information please view the faculty profile of Jane Wu, MD, PhD or visit the Wu Lab website.

Recent Publications

View a full list of publications by Jane Wu at PubMed.

Contact Us

Email Jane Wu, MD, PhD 

Phone: 312-503-0684

 

 Jennifer Wu Lab

Understanding the mechanisms of cancer immune evasion and development of novel immune therapy

Research Description

Dr. Wu's goal to better understand prostate cancer and cancer in general and to find a better treatment for the untreatable terminal diseases, her current research focuses on the following aspects:  

  1. Understanding the universal mechanisms of cancer immune evasion and development of novel cancer immunotherapy with specific focus on the NKG2D signaling pathways; 
  2. Understanding why immunotherapy is not effective in prostate cancer and how to make it work with understanding underlying mechanisms of resistance; 
  3. Discovering biomarkers to distinguish progressive vs. indolent prostate cancer to direct clinical decision making on treatment options; 
  4. Understanding mechanism underlying immunotherapy (specifically, immune checkpoint inhibitor-therapy) induced toxicity and developing mechanism-direct personalized treatment for cancer patients to alleviate toxicity and to improve clinical outcomes.  

For more information please view the faculty profile of Jennifer Wu, PhD.

Recent Publications

Dhar P, Basher F, Ji Z, Huang L, Qin S, Wainwright DA, Robinson J, Hagler S, Zhou J, MacKay S, Wu JD. Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation. Commun Biol. 2021 Jul; 4(1): 905-.

Basher F, Dhar P, Wang X, Wainwright DA, Zhang B, Sosman J, Ji Z, Wu JD. Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy. J Hematol Oncol. June 2020.

Zhang J, Larrocha PS, Zhang B, Wainwright D, Dhar P, Wu JD. Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC + tumors respond to PD1/PD-L1 blockade therapy. J Immunother Cancer.  August 2019.

View a full list of publications by Jennifer Wu at PubMed

Contact Us

Email Jennifer Wu, or phone at 312-503-1521

 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

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