Jian Yu, PhD
Professor of Pathology
Dr. Yu is a member of the University of Pittsburgh Cancer Institute, an affiliated member of the Division of Experimental Pathology, and training faculty of the Cellular and Molecular Pathology Graduate Training Program and Pitt-CMU MSTP training program.
Hillman Cancer Center
Research Pavilion Suite 2.26H
5117 Centre Avenue
Pittsburgh, PA 15213
Office Phone: 412-623-7786
- BS - Sichuan University, Chengdu, Sichuan, P.R. China, 1991
- PhD - Johns Hopkins University, 2001
The gastrointestinal epithelium is the fastest renewing tissue in adult mammals and maintained by tissue specific stem cells. Both cell-intrinsic programs and environmental cues critically regulate intestinal homeostasis and regeneration following injury via coordinated stem cell activation, lineage specification and barrier functions. Mounting evidence indicates that intestinal stem cell (ISC) dysfunction plays a key role in GI pathology ranging from inflammation, cancer and age-associated diseases. Yu lab has been elucidating cell death mechanisms and targets aimed for selective protection of normal intestinal stem cells and killing of cancerous stem cells. There are currently two major research areas in the lab.
Intestinal stem cell protection Damage to intestinal stem cells leads to acute and chronic GI injury, and increased risk for inflammation and cancer. Our work indicates that excessive cell death associated with different forms of DNA damage contributes to intestinal and stem cell injury and carcinogenesis via both p53-dependent and independent mechanisms. We are exploring novel interactions of cell death and the DNA damage response in intestinal injury and regeneration in vivo, and pharmacologic approaches for ISC protection by blocking p53-dependent apoptosis.
Colon cancer therapy Cell death evasion is a common feature of cancer linked to immune evasion. We have previously identified and extensively studied the Bcl-2 family protein PUMA as a critical mediator of apoptosis induced by a wide range of anticancer drugs in colon cancer cells. We are currently exploring driver-dependent addictions in colon cancer to improve therapeutic responses by increasing immunogenic cell death. Additional studies include rational combination of agents, underlying mechanisms, and biomarker discovery for predicting therapeutic responses.
The long term goal of Dr. Yu's research is to identify novel mechanisms, targets and agents to combat GI pathology through cell death manipulation. Diverse approaches are employed, including molecular and cell biology, imaging, somatic knockout and knockin cancer cells, 3D primary intestinal crypt cultures, genetically engineered mouse models, computational biology, drug discovery and clinical samples.
- Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B. PUMA induces the rapid apoptosis in colorectal cancer cells. Mol. Cell 2001 Mar 30;7(3):673-82. (Featured in Nature Reviews of Molecular Cell Biology 2:319, 2001)
- Yu J, Wang Z, Kinzler KW, Vogelstein B, Zhang L. PUMA mediates the apoptotic response to p53 in colorectal cancer cells. Proc. Natl. Acad. Sci. USA 2003 Mar 100:1931-1936.
- Qiu W, Carson-Walter EB, Liu H, Epperly M, Greenberger JS, Zambetti, GP, Zhang L, Yu J. PUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome. Cell Stem Cell. 2008 Jun 5;2(6):576-83. PMID:22751125. PMCID:PMC3751796. (Featured in Cell Stem Cell 2: 517-518, 2008 and Nature Biotechnology 26 (7): 777, 2008).
- Mustata G, Li M, Zevola N, Bakan A, Zhang L, Epperly M, Greenberger JS, Yu J*, Bahar I. Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death. Curr Top Med Chem. 2011;11(3):281-90. * Co-Corresponding author. PMCID: PMC308601154.
- Leibowitz BJ, Wei L, Zhang L, Ping X, Epperly M, Greenberger J, Cheng T, Yu J. Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice. Nat Commun. 2014 Mar 18;5:3494. PMID:24637717. PMCID: PMC4327858.
- Leibowitz B, Qiu W, Buchanan ME, Zou F, Vernon PV, Moyer MP, Yin X, Schoen RE, Yu J*, Zhang, L*. BID mediate selective killing of APC-deficient cells in intestinal tumor suppression by non-steroidal anti-inflammatory drugs. Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16520-5. * Co-corresponding author. PMID: 25368155. PMCID: PMC4246283.
- Wang X, Wei L, Cramer J, Leibowitz B., Judge C, Epperly M, Greenberger J, Wang F, Li L, Stelzner M, Dunn J, Martin M, Lagasse E, Zhang L, Yu J. Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation. Sci Rep. 2015 Apr 10;5:8566. PMID: 25858503. PMCID: PMC4392360.
- He K, Zheng X, Li M, Zhang L, Yu J. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation. Oncogene. 2015 Apr 13. PMID: 25867072. PMCID: PMC4603992.
- Brown MF, Leibowitz BJ, Chen D, He K, Zou F, Sobol RW, Beer-Stolz D, Zhang L, Yu J. Loss of Caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis. Cell Death Dis. 2015 Apr 23;6:e1729. PMID: 25906152. PMCID: PMC4650537.
- He K, Chen D, Ruan H, Li X., Tong J, Xu X, Zhang L, Yu J. BRAFV600E-dependent Mcl-1 stabilization leads to Everolimus resistance in colon cancer cells. Oncotarget. 2016 June 24. doi: 10.18632/oncotarget.10277. PMID: 27351224.
- Wei L, Leibowitz BJ, Wang X, Epperly M, Greenberger J, Zhang L, Yu J. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. J Clin Invest. 2016 Oct 4. PMID: 27701148. (Featured in Nature Reviews Gastroenterology & Hepatology, doi:10.1038/nrgastro.2016.175).
(Last updated on 12/10/2016)