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) understanding the mechanisms of the NF1- CDKN2A- and PRC2-loss mediated oncogenic transformation in malignant peripheral nerve sheath tumor (MPNST); 3) understanding oncogene (e.g. ALK and other kinases) activation through alternative transcriptional initiation in a variety of cancer types.