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Northwestern University Feinberg School of Medicine
Department of Dermatology
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Skin Cancer

Skin cancers are the most common human neoplasias. Within the Department of Dermatology, laboratories are conducting both basic and translation research on each of these distinct types of cutaneous cancers.

 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

 Jaehyuk Choi Lab

Genetic basis of inherited and acquired immunological disorders and skin cancer.

Research Description

We employ cutting-edge genomics approaches to identify the genetic basis of inherited and acquired immunological disorders and skin cancer.

As an example, we have recently identified the genes and mutations underlying cutaneous T cell lymphoma, an incurable non-Hodgkin lymphoma of skin-homing T cells. The genes are components of the DNA damage, chromatin modifying, NF-kB and the T cell receptor signaling pathways. We are currently employing a comprehensive approach using human tissues and animal models to investigate the functions of these genes. We are confident these studies will allow us to elucidate the pathophysiology of this cancer and lead to the identification of novel therapeutic targets.

Work in the lab is funded by National Cancer Institute, Dermatology Foundation, American Skin Association and American Cancer Society. See the work of the Choi lab in the news. For further information, please also see Dr. Choi's faculty profile.

Publications

See Dr. Choi's publications on PubMed.

Contact

Contact Dr. Choi.

 Robert Lavker Lab

Investigating the biology of epithelial stem cells and how stem cells are regulated by microRNAs.

Research Description

The Lavker laboratory focuses on the biology of epithelial stem cells and the roles of microRNAs (miRNAs) in regulating epithelial homeostasis. In collaboration with Tung-Tien Sun (NYU Medical School), the lab identified and characterized stem cells of the epidermis, hair follicle and corneal epithelium. We have demonstrated that the hair follicle stem cells (located in the bulge region of the follicle) are pluripotent; capable of forming the hair shaft as well as the epidermis. Collectively, these studies have been of major importance for their implications regarding tissue regeneration, hair follicle growth, and carcinogenesis.

Initial investigations on microRNAs (miRNAs) focused on corneal epithelial-preferred miRNAs. Specifically, miR-205 undergoes a unique form of regulation through an interaction with the corneal-preferred miR-184 to maintain SHIP2 levels. SHIP2, a lipid phosphatase, is a target of miR-205, which enhances keratinocyte survival through PI3K-Akt signaling. This miRNA also positively regulates keratinocyte migration by altering F-actin organization and decreasing cell-substrate adhesion.

Recently, the lab has focused on miR-31, which targets factor inhibiting hypoxia-inducible factor-1 (FIH-1). FIH-1 impairs epithelial differentiation via attenuation of Notch signaling. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus. This provides a rationale for development of treatment regimens in patients with diseases affecting abnormal epithelial differentiation (e.g., psoriasis) using inhibitors of FIH-1.

We have also demonstrated that miR-31 targets FIH-1 to positively regulate corneal epithelial glycogen metabolism, which results in the accumulation of glycogen. Increased glucose in the form of glycogen may be a mechanism by which the corneal epithelium is able to withstand periods of hypoxia during eyelid closure or extended contact lens wear. Thus miR-31 may function as a novel means if protecting the corneal epithelium from hypoxic stress.

Most recently, the laboratory has defined the microRNA expression patterns of the stem cell-enriched limbal basal cells and has begun to identify targets that are unique to the limbal epithelium. This should lead to an understanding of how miRNAs regulate epithelial stem cells.

Publications

For publication information and more, see the Lab faculty’s profiles:

Robert Lavker, PhDHan Peng, PhD

Contact Lavker Lab

Contact the Lavker Lab at 312-503-2043 or visit us on campus in the Montgomery Ward Building, 303 E. Chicago Avenue, Ward 9-120, Chicago, Illinois, 60611.

Faculty

Robert M. Lavker, PhD, Han Peng, PhD

Postdoctoral Fellows

Nihal Kaplan, PhD

Technician

Wending Yang, PhD

Visiting Scholar

Junyi Wang, PhD

 Amy S. Paller Lab

a) Ganglioside modulation in diabetic wound healing and epidermal innervation abnormalities.

b) Impact of adiponectin on psoriasis severity and immunophenotype in obesity.

c) Utilizing siRNA and antisense Spherical Nucleic Acids (SNAs) to treat skin disorders.

Research Description

The Paller laboratory primarily focuses on inflammatory skin diseases and the development of novel therapeutic approaches. A long-term interest is the role in keratinocytes and other skin cells of lipid raft glycosphingolipids called gangliosides. The laboratory has shown that modulation of ganglioside content genetically (including by SNAs, see below) and biochemically profoundly affects skin cell function through affecting cell signaling. We have found that increases in membrane ganglioside expression suppress function of the epidermal growth factor receptor, insulin receptor, insulin-like growth factor receptor-1, and integrins, whereas depletion of ganglioside content stimulates receptor activation. The most recent translational research has involved use of ganglioside depletion using genetic and biochemical approaches to accelerate diabetic wound healing in human 3D and mouse diet-induced obese models, as well as to reverse the innervation abnormalities in back skin and footpads in diabetic models. 

A second area of interest is in immune abnormalities in psoriasis, with an emphasis on the impact of obesity. In both humans and mouse models, obesity increases the severity of psoriasis. The Paller laboratory has shown that the pro-inflammatory effect of obesity depends on reduction of adiponectin and that adiponectin mimetics reverse the tending towards psoriasis exacerbation through suppression of PPAR-gamma activation, reduction of Th17 skewing and increases in Treg cell activity.

Finally, an intense focus of investigation is topical application of siRNA and antisense spherical nucleic acids (SNAs) as a novel therapy for skin disorders. SNAs, in which the oligomers are densely arrayed around a central gold nanoparticle, were originally developed by the Mirkin laboratory at Northwestern. We have found that SNAs are: a) readily taken up into cultured keratinocytes; b) able to penetrate through the mouse and human epidermal barriers after application in a common moisturizer; c) suppress genes at nM to pM concentrations; d) have minimal off-target or immune effects after application; and e) to date, have shown no systemic or cutaneous toxicity. These studies have moved forward into showing improvement after topical application of SNAs directed against ganglioside GM3 synthase (diabetic wound healing), TNF or IL17RA or, using a bispecific, both targets (for psoriasis), and TGF-beta or CTGF for scars. SNAs for psoriasis have advanced to human trials.

Publications

For publication information and more, see Amy Paller's, MD/MS faculty profile.

Contact Paller Lab

Contact the Paller Lab at 312-503-0298 or visit us on campus in the Montgomery Ward Building at 303 E. Chicago Avenue, Ward 9-070, Chicago, Illinois, 60611.

Faculty

Amy S. Paller, MD/MS

Senior Research Associate

Michael Bonkowski, PhD

Research Associate Professor

Xiao-Qi Wang, MD/PhD

Postdoctoral Fellows

Haoming Liu, PhD, Thomas Holmes, PhD

Visiting Predoctoral Fellow

Kevin Kwan

Technician

Kyle Dombeck

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