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Gen-Sheng Feng


Molecular Signaling in Cancer, Metabolism and Stem Cells

At the heart of cancer research is the elucidation of oncogenes and tumor suppressor genes (or anti-oncogenes), which has been a driving force in the cancer field for several decades. Most recent studies in this and other labs have revealed dual roles of genes in promoting and suppressing hepatocellular carcinoma (HCC). Deciphering the “paradoxical” effects of these genes may provide a fresh view on the fundamental mechanisms of carcinogenesis, which can lead to development of mechanism-based therapeutics for HCC. Our current focuses are on delineating genetic and epigenetic interactions and cell-cell communications that drive hepatocarcinogenesis. We are very interested in isolating and characterizing cancer stem cells, CSCs (or tumor-initiating cells, TICs) in the liver, and in dissecting the dynamic interplay between tumors and the hepatic microenvironment. Efforts are also being devoted to elucidation of metabolic changes in tumor cells and to search of biomarkers for early diagnosis of liver cancers.

We are also interested in deciphering the common and distinct biochemical pathways in self-renewal of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), with the objective of understanding how an HSC pool is maintained throughout life, and with the ultimate goal of identifying novel targets for elimination of LSCs.

Another focus is on dissecting the signaling events involved in metabolic disorders such as obesity and diabetes. Ongoing experiments are aimed at understanding the intertwining of leptin and estrogen signaling cascades, to illustrate why estrogen has a leptin-like effect in control of metabolism, why postmenopausal women have the tendency to develop obesity, and why obesity promotes breast cancer. Whereas obesity has become a serious health problem in developed countries worldwide, one ongoing project in the lab is to investigate an indispensable physiological role of adipogenesis and adipose tissue in mammals, as revealed by the most recent data obtained in this lab.


  • Zhu HH, X Luo, K Zhang, J Cui, H Zhao, Z Ji, Z Zhou, J Yao, L Zeng, K Ji, WQ Gao, ZY Zhang, and GS Feng (2015). Shp2 and Pten have antagonistic roles in myeloproliferation but cooperate to promote erythropoiesis in mammals. Proc Natl Acad Sci USA 112, 13342-7.
  • Deng Z, S Ma, H Zhou, Aiping Zang, Y Fang, T Li, H Shi, M Liu, M Du, PR Taylor, HH Zhu, J Chen, G Meng, F Li, C Chen, Y Zhang, X Zhang, E Pearlman, X Li, GS Feng and H Xiao (2015). Tyrosine phosphatase SHP2 mediates Dectin-induced SYK activation and anti-fungal TH17 response. Nature Immunol. 16, 642-52.
  • Li S, DDF Hsu, B Li, X Luo, N Alderson, L Qiao, L Ma, HH Zhu, Z He, K Suino-Powell, K Ji, J Li, J Shao, HE Xu, T Li, and GS Feng (2014). Cytoplasmic tyrosine phosphatase Shp2 coordinates hepatic regulation of bile acid and FGF15/19 signaling to repress bile acid synthesis. Cell Metabolism 20, 320-332 (recommended by Faculty 1000, Previewed, Cell Metabolism 20, 203-204.
  • He Z, HH Zhu, TJ Bauler, J Wang, T Ciaraldi, N Alderson, S Li, MA Raquil, K Ji, S Wang, J Shao, R Henry, PD King, and GS Feng (2013). Non-receptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase. Proc Natl Acad Sci USA. 110, E79-88.
  • He Z, SS Zhang, Q Meng, S Li, HH Zhu, MA Raquil, N Alderson, H Zhang, J Wu, L Rui, D Cai, and GS Feng (2012). Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Mol Cell Biol 32, 1867-1878, 2012. PMCID 3347413
  • Feng GS (2012).Conflicting roles of molecules in hepatocarcinogenesis: paradigm or paradox (Invited Review). Cancer Cell 21:150-154.
  • He Z, SS Zhang, Q Meng, S Li, HH Zhu, MA Raquil, N Alderson, H Zhang, J Wu, L Rui, D Cai, and GS Feng (2012). Shp2 controls female body weight and energy balance by integrating leptin and estrogen signals. Mol Cell Biol 32:1867-1878.
  • Qian, YW,Y Chen, W Yang, J Fu, J Cao, JJ Zhu, B Su, T Luo, YB Ren, RY Dai, JJ Li, XF Zhao, MC Wu, GS Feng, and HY Wang (2012). p28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis. Gastroenterology 142:1547-1558.
  • Huang J, Yan J, Zhang J, Zhu S, Wang Y, Shi T, Zhu C, Chen C, Liu X, Cheng J, Mustelin T, Feng GS, Chen G, and Yu J (2012). SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. Nature Commun 3:911.
  • Huang H, Woo AJ, Waldon Z, Schindler Y, Moran TB, Zhu HH, Feng GS, Steen H, and Cantor AB (2012). A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev 26:1587-1601.
  • Zhu, HH, K Ji, N Alderson, Z He, S Li, W Liu, DE Zhang, L Li, and GS Feng (2011). A Kit-Shp2-Kit signaling axis regulates a functional hematopoietic stem and progenitor cell pool. Blood 117:5350-5361.
  • Bard-Chapeau EA, S Li, J Ding, SS Zhang, HH Zhu, F Princen, DD Fang, T Han, B Bailly-Maitre, V Poli, H Wang and GS Feng (2011). PTPN11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19:629-639.
  • Zhang SS, E Hao, J Yu, W Liu, J Wang, F Levine, and GS Feng (2009). Coordinated regulation by Shp2 tyrosine phosphatase of signaling events controlling insulin biosynthesis in pancreatic beta-cells. Proc Natl Acad Sci USA 106:7531-7536. PMCID 2678606
  • Ke K, EE Zhang, K Hagihara, D Wu, YH Pang, R Klein, T Curran, B Ranscht, and GS Feng (2007). Deletion of Shp2 in the brain leads to defective proliferation and differentiation in neural stem cells and early postnatal lethality. Mol Cell Biol 27:6706-6717.
  • Ke Y, D Wu, F Princen, T Nguyen, Y Pang, J Lesperance, WJ Muller, RG Oshima, and GS Feng (2007). Role of Gab2 in mammary tumorigenesis and metastasis. Oncogene 26:4951-4960.
  • Bard-Chapeau, EA, J Yuan, N Droin, S Long, EE Zhang, TV Nguyen, and GS Feng (2006). Concerted functions of Gab1 and Shp2 in liver regeneration and hepatoprotection. Mol Cell Biol 26:4664-4674.
  • Chapeau E, AL Hevener, S Long, EE Zhang, JM Olefsky and GS Feng (2005). Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Nature Medicine 11:567-571.
  • Zhang EE, E Chapeau, K Hagihara and GS Feng (2004). Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci USA 101:16064-16069.
  • You M, LM Flick, DH Yu, and GS Feng (2001). Modulation of the nuclear factor-kappaB pathway by Shp-2 tyrosine phosphatase in interleukin (IL)-6 induction by IL-1 or tumor necrosis factor. J Exp Med 193:101-109.
  • Feng GS, and T Pawson (1994). Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction (review article). Trends Genet 10:54-58.
  • Feng GS, CC Hui, and T Pawson (1993). SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259:1607-1611.


Dr. Feng received his PhD degree at Indiana University Bloomington and did a postdoctoral fellowship at the University of Toronto.