Zhong Yun, PhD
Assistant Professor, Department of Therapeutic Radiology
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zhong.yun@yale.edu Phone: 203.737.2183 Appt Phone: Fax: 203.785.6309 Yale University School of Medicine Department of Therapeutic Radiology P.O. Box 208040 New Haven, Connecticut 06520-8040 |
Degrees/Education:
B.Engineer. Hefei University of Technology, China (1983)
M.S. Institute of Chemistry, Chinese Academy of Sciences, China (1986)
Ph.D. University of Texas M.D. Anderson Cancer Center, Texas (1996)
Faculty Appointments:
Assistant Professor, Yale University School of Medicine, Department of Therapeutic Radiology (2003-Present)
Research Interests:
Our overall research interest is to investigate the mechanisms by which tissue microenvironment, especially hypoxia, regulates the important biological processes including cellular differentiation, metabolism, tumor progression and tumor response to therapy. Our current focuses are (1) the role of hypoxia in the regulation of stem/precursor cell differentiation, (2) the effects of hypoxia on cancer cell differentiation, malignant progression and response to therapy, (3) the role of HIF pathway in adipocytes and myocytes, especially in the regulation of energy homeostasis, and the pathogenesis of obesity and/or type 2 diabetes.
Oxygen is essential to all aerobic life forms on earth. In addition to its role in energy metabolism, oxygen has broad biological impact from embryogenesis to adulthood. This notion is strongly supported by the fact that mammalian embryos develop in a low oxygen or hypoxic environment (≤3% O2) during the first trimester. Furthermore, recent studies from us and other laboratories have shown that oxygen can directly regulate the differentiation of stem/precursor cells, and may participate in the maintenance of stem cells in the stem cell niche.
Because of the limited oxygen concentration in the air, oxygen-sensing mechanisms exist from bacterial to mammalian cells to deal with hypoxia or oxygen deficiency. The hypoxia-signal transduction mediated by the hypoxia-inducible factor (HIF) is highly conserved from fly to mammalian cells. In mammals, hypoxia can occur due to physiological or pathological stresses, such as strenuous physical exercise, adventure to high altitude, cardio/pulmonary malfunction, decreased endothelial functions, tissue wounds or damage, and cancer. Hypoxia has significant effects on the metabolism of ischemic tissues, wound healing, malignant progression of cancer and therapeutic response of cancer cells.
Hypoxia and the regulation of cancer cell differentiation. Hypoxia occurs in majority of solid tumors. Tumor hypoxia is strongly correlated with advanced disease stage and poor clinical outcome. This is, in part, due to increased genomic instability in hypoxic tumor cells and enhanced resistance of hypoxic tumors to radio- and chemo-therapy. Recently, increasing amounts of evidence suggest that hypoxic tumor cells tend to be poorly differentiated. We hypothesize that hypoxia inhibits cancer cell differentiation and thus arrests tumor cells in their undifferentiated state. Our hypothesis represents a novel approach to the understanding of tumor progression under hypoxic conditions. It is widely accepted that tumorigenic or tumor-initiating cells posses stem cell-like properties. Poorly differentiated tumor cells are almost always more tumorigenic and more malignant than their well-differentiated counterparts. The extensive proliferative potentials and long lifespan will allow the undifferentiated tumor cells to accumulate stable genetic and epigenetic changes that eventually confer the malignant phenotype. Therefore, hypoxia-mediated differentiation arrest of tumorigenic cells provides a platform that allows continuous accumulation and perpetuation of both genetic and epigenetic changes that result in tumor malignancy. Currently, we are using several tumor model systems to test this hypothesis. These studies will have the potentials to provide new approaches toward effective therapy for solid tumors, e.g. by specifically targeting the undifferentiated cancer stem cell population in the hypoxic regions.
The HIF pathway and metabolism: Implications in obesity and diabetes.
Obesity has become a world-wide epidemic and is associated with more than 30 human diseases including type 2 diabetes, cardiovascular disease, and cancer. Adipose tissue plays a critical role in the development of obesity and other metabolic syndromes. The HIF pathway plays a key role in energy metabolism. In addition to O2 deficiency, insulin receptor signaling can induce the accumulation of the HIF-1 protein. HIF-1 enhances the transcription of many key genes involved in glucose metabolism and angiogenesis. These two critical functions predict an essential role for HIF-1 in adipose tissue functions because adipose tissue is the main energy depot and can grow very rapidly to accommodate excessive amounts of energy. However, the biological functions of HIF-1 in adipocytes have not been well studied. We were the first to investigate the mechanisms by which HIF-1 regulates the adipogenic differentiation. We have found that HIF-1 is both necessary and sufficient to inhibit the adipogenic differentiation of preadipocytes. Mechanistically, PPAy2 transcription is repressed by the HIF-1 target gene DEC1/Stra13. Furthermore, hypoxia arrests preadipocytes in their stem/precursor state. We have generated a genetic mouse model to test the hypothesis that HIF plays an important role in the development and functions of adipose tissue, as well as in the pathogenesis of obesity and type 2 diabetes. In addition, we are also investigating the role of HIF in the regulation of muscle cell differentiation and metabolic functions of myocytes. These studies will have the potential to elucidate novel mechanisms by which the HIF pathway regulates energy homeostasis. This research will have the potential to establish HIF as a therapeutic candidate for the treatment of metabolic syndromes related to obesity and diabetes.
Selected PubMed article listing
Selected Publications:
Yun, Z., Lin, Q., and Giaccia, A.J. (2005) Adaptive Myogenesis under Hypoxia. Mol. Cell. Biol. 25:3040-3055.
Swiersz, L., Giaccia, A.J. and Yun, Z. (2004) Oxygen-Dependent Regulation of Adipogenesis. Methods Enzymol. 381:387-95.
Yun, Z. and Giaccia, A.J. (2003) Tumor Deprivation of Oxygen and Tumor Suppressor Gene Function. Methods Mol. Biol. 223:485-504.
Yun, Z., Maecker, H. L., Johnson, R. S. and Giaccia, A. J. (2002) Inhibition of PPAR g 2 Gene Expression by the HIF-1 Regulated Gene DEC1/Stra13: A Mechanism for Regulation of Adipogenesis by Hypoxia. Developmental Cell 2:331-341.
Maecker, H. L., Yun, Z.; Maecker, H. T., and Giaccia, A. J. (2002) Epigenetic Changes in Tumor Fas Levels Determine Immune Escape and Response to Therapy. Cancer Cell. 2:139-148.
Laderoute, K. R., Alarcon, R. M., Brody, M. D., Calaoagan, J. M., Chen, E. Y., Knapp, A. M., Yun, Z., Denko, N. C., and Giaccia A. J. (2000) Opposing Effects of Hypoxia on Expression of the Angiogenic Inhibitor Thrombospondin 1 and the Angiogenic Inducer Vascular Endothelial Growth Factor. Clin.Cancer Res. 6:2941-2950.
Yun, Z.; Smith, T. W.; Menter, D. G.; McIntire, L. V.; and Nicolson, G. L. (1997) Differential Adhesion of Metastatic RAW117 Large-Cell Lymphoma Cells under Static or Hydrodynamic Conditions: Role of Integrin a v b 3. Clin. Exp. Metastasis 15:3-11.
Yun, Z.; Menter, D. G.; and Nicolson, G. L. (1996) Involvement of Integrin av b3 in Liver Metastasis of RAW117 Large-Cell Lymphoma. Cancer Res. 56:3103-3111.
Smith, T. W.; Yun, Z.; Menter, D. G.; McIntire, L. V.; and Nicolson, G. L. (1996) Computerized Analysis of Tumor Cell Interactions with Extracellular Matrix Proteins and Endothelial Cells Under Laminar Flow. Biotech. Bioengineer. 50:598-607.
Nicolson, G. L.; Menter, D. G.; Herrmann, J. L.; Yun, Z.; Cavanaugh, P. G.; and Marchetti, D. (1996) Brain metastasis: role of trophic, autocrine and paracrine factors in tumor invasion and colonization of the central nervous system. Curr. Topics Microbio. Immunol. 213:89-115.
Nicolson, G. L.; Menter, D. G.; Herrmann, J. L.; Cavanaugh, P. G.; Jia, L.-B.; Hamada, J.; Yun, Z.; and Marchetti, D. (1994) Tumor metastasis to brain: role of endothelial cells, neurotrophins and paracrine growth factors. Cri. Rev. Oncogenesis 5:451-471.
