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INVESTIGATOR PROFILES |
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STAFF SCIENTIST DIRECTOR CONTACT
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Michael Shtutman, Ph.D.Research FocusThe goal of the work in my laboratory is to apply contemporary functional genomic technology to critical problems in cancer research so as to identify the molecular pathways through which cancer cells progress to more aggressive states. I hope to utilize this information to develop new therapies that target these pathways and bring the cancer cells under control. Currently, my research focuses on two areas. The first area is that of the cancer cell metastatic process. This is an important problem and it encompasses all human tumor systems since most cancer patient deaths are due to metastatic disease. We have long known that cell-cell adhesion complexes regulate many aspects of tumor cell behavior, from cell migration to cell proliferation and survival. Adherens junctions are structures that mediate cell-cell adhesion. These structures allow cells to sense their neighbors and, in the normal state, they limit the growth and motility of individual cells and they are required for establishing appropriate tissue architecture. These structures consist of transmembrane protein complexes that form around cadherin receptors. The cytoplasmic domains of cadherins, in turn, bind to various catenin proteins that anchor the surface junctions to the cytoskeleton and they participate in cellular signaling processes. In turn, these complexes are regulated by proteins of the immunoglobulin-like superfamily, especially those of the L1-subfamily. My research interests focuses on characterizing the role of the L1-subfamily proteins in regulating gene expression in cancer cells and their ability to migrate and metastasize. Based upon our research, I have proposed a model through which a small variation of adherence-dependent signaling can increase the invasiveness of a cancer cell (Figure1). This model explains how expression of L1-CAM can activate a feedback loop that allows cancer cells to migrate out of the original tumor. Additionally, I am utilizing functional genomics to help explain how human prostate cancer cells acquire resistance to hormonal therapy. Prostate cancer is a disease that develops under the influence of androgenic (male) steroids and treatments for the advanced form of the disease rely on therapies that deplete the patient of androgens. Metastatic prostate cancer lesions often shrink after hormone (androgen-ablation) therapy and the proliferative index of the tumor cells drastically decline. Unfortunately, hormone therapy often fails and the patient recurs with a form of the disease that continues to grow despite the lack of androgens. The cancer cells in these patients have a hyperactive androgen signaling system characterized by high expression of androgen receptor (AR) mRNA and protein and by “promiscuous” transcriptional activity of the AR protein in an androgen-depleted environment. We are using a high throughput functional genomic approach to identify new molecular pathways involved in regulation of activity of androgen receptor. Our strategy employs androgen-responsive cancer reporter cell lines and we are utilizing “gene-knockout” technology involving prostate cancer-specific lentiviral shRNA libraries to identify the genes that enable androgen signaling in an androgen-free environment (Figure 2). We are also collaborating with Dr. Igor Roninson in using functional genomic approaches to identify genes essential for tumor cell growth, as potential targets for new anticancer drugs. Selected Publications (View)
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