Weihua Zhang, MD, PhD
Survival Mechanisms of Cancer Cells
The Kinase-Independent Survival Function of
EGFR in Cancer Cells
The membrane tyrosine kinase epithelial growth factor receptor (EGFR) frequently exhibits increased kinase activity in tumors of epithelial origin. However, small molecule inhibitors of EGFR have yet to show therapeutic effects in clinical trials, begging the question of whether EGFR tyrosine kinase activity is the only appropriate target. Our studies have shown that EGFR, in a kinase-independent manner, helps to maintain the basal intracellular glucose level of cancer cells by stabilizing the glucose transporter, SGLT1. Cancer cells require more glucose than normal cells for survival. Thus, the kinase-independent activity of EGFR, which maintains glucose uptake in cancer cells, might serve as an effective target for cancer therapy. Our current efforts are directed toward further exploring the interaction of SGLT1 and EGFR as well as how this interaction affects the metabolism, survival and growth of cancer cells.
Identification of Tumor-Initiating Cells in Urological Tumors
The failure of cancer therapy in the long term is often attributed to tumor cell heterogeneity. Specifically, many hypothesize that a subpopulation of tumor cells resistant to therapeutic agents may serve as the source of cells for tumor relapse and metastasis after treatment. The identification and characterization of such a tumor-initiating cell holds great promise as a way to develop more effective therapies. Thus, another goal of my laboratory is to isolate tumor-initiating cells of urological tumors.
The Role of Apoptotic Cells in the Angiogenesis of Solid Tumors
Angiogenesis, the development of new blood vessels from preexisting vessels, is crucial to tissue growth, repair, and maintenance. This process begins with the formation of endothelial cell sprouts followed by the proliferation and migration of neighboring endothelial cells along the preformed extensions. The initiating event and mechanism of sprouting is not known. Previously we found that the phenotypic expression of negatively charged membrane surface in apoptotic cells initiates the formation of directional endothelial cell sprouts that extend toward the dying cells by a mechanism that involves endothelial cell membrane hyperpolarization and cytoskeleton reorganization but is independent of diffusible molecules. This finding suggests that apoptotic cells are angiogenic. Currently we are investigating the molecular mechanisms of the recognition of distant apoptotic cells by endothelial cells in vitro and the role of apoptotic cell initiated angiogenesis in the development of drug resistance during cancer therapy.
Selected Publications: (my name appears as Zhang Weihua in all my publications)
- Xu, S and Weihua, Z. Knocking down EGFR, but not inhibiting its kinase activity, sensitizes prostate cancer cells to chemotherapeutic reagents. 2008 (manuscript).
- Weihua, Z., Tsan, R., Lin, Q. and Fidler, I.J. Solid tumor formation from a single cell. 2008 (manuscript).
- Weihua, Z., Tsan, R., Fidler, I. J. and Hung, M-C. Survival of Cancer Cells is Maintained by EGFR independent of its kinase activity. Cancer Cell, 2008 (In press)
- Weihua Z., Tsan R., Do-Hyun Nam, Lu W. and Fidler, IJ. Loss of Adhesion in the Circulation Converts Amelanotic Metastatic Melanoma Cells to Melanotic by Inhibition of AKT. Neoplasia, 8(7): 543-550, 2006.
- Weihua, Z., Tsan, R., Schroit, A. J., and Fidler, I. J. Apoptotic cells initiate endothelial cell sprouting via electrostatic signaling. Cancer Res., 65(24): 11529-11535, 2005. *Article selected for Highlight in Science 311:16, 2005.