It is well recognized that the cellular context contributes to susceptibility to oncogenic transformation mediated by different “driver” oncogenes. The focus of our laboratory is to discover and understand the critical genetic and epigenetic factors that determine the cellular-context-dependent oncogenesis in distinct cancer types, with a primary focus on sarcoma and melanoma. We use multimodality approaches, including transcriptome analyses, epigenome mapping, and gene-expression-based high-throughput screens, as well as murine models to understand the mechanisms of pathogenesis and to develop biomarkers and targeted therapies based on insight into disease pathogenesis.
As an example, the interstitial cells of Cajal (ICC) give rise to one of the most common human sarcomas — gastrointestinal stromal tumor (GIST). ICCs are particularly susceptible to oncogenesis mediated by gain-of function mutations in the KIT receptor tyrosine kinase, as patients with germline mutations of KIT develop GIST but not other malignancies. We have recently discovered that ETV1, an ETS family transcription factor, is a lineage-specific survival factor of ICCs. It is required for normal ICC development and for growth and survival of GIST in vitro and in vivo. We have further demonstrated that ETV1 regulates a lineage-specific transcriptional program well conserved in ICC and GIST. The ETV1 protein is stabilized by the MAP kinase signaling pathway downstream of KIT signaling and it cooperates with mutant KIT in GIST oncogenesis. These studies indicate that ETV1 defines the optimal cellular context for mutant KIT-mediated oncogenesis in GIST, and provide an explanation for why familial GIST patients and genetically engineered mice with germline-activating KIT mutations develop malignancy (GIST) of the ICC lineage, but not of other KIT-regulated cell lineages. They also suggest ETV1 as a novel biomarker in GIST and an alternative therapeutic target in GIST.
Our current efforts are focused on the following areas: 1) elucidating the genetic and epigenetic mechanisms involved in the regulation of ETV1-mediated oncogenic transcriptome in GIST and comparing results with data for other ETS-dependent malignancies; 2) characterizing the molecular mechanisms of ETV1 protein stability regulation by the MAP kinase signaling pathway; and 3) developing novel strategies to target ETV1 in imatinib-resistant GIST and other ETV1-dependent malignancies.
Yan Z, Chi P, Bibb JA, Ryan TA, Greengard P. Roscovitine: a novel regulator of P/Q-type calcium channels and transmitter release in central neurons. J Physiol. 2002 May 1;540(Pt 3):761-70.
Chi P, Greengard P, Ryan TA. Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Neuron. 2003 Apr 10;38(1):69-78.
Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T, Fletcher JA, Dewell S, Maki RG, Zheng D, Antonescu CR, Allis CD, Sawyers CL. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010 Oct 14;467(7317):849-53. doi: 10.1038/nature09409. Epub 2010 Oct 3.
Chen Y, Shamu T, Chen H, Besmer P, Sawyers CL, Chi P. Visualization of the interstital cells of cajal (ICC) network in mice. Journal of Visualized Experiments, JoVE 2011; Jul27;(53).pii2802. doi10.3791/2802.
Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S, Gao D, Sirota I, Carver BS, Wongvipat J, Scher HI, Zheng D, Sawyers CL. (2013) ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nature Medicine. In press
Kimmel Scholar Award, Sidney Kimmel Foundation (2012)
Research Grant, Sarcoma Foundation of America (2012)
Grant, GIST Cancer Awareness Foundation (2012)
Director’s New Innovator Award, National Institutes of Health (2012)
Clinical Scientist Development Award, National Instistutes of Health (2011)
Ping Chi, a physician-scientist and member of the Human Oncology and Pathogenesis Program, studies genetic and epigenetic changes that cause cancer.
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