Functional genomics and human cell transformation
My work as a physician-scientist involves both the care of cancer patients and biomedical research directed toward a greater understanding of the mechanisms involved in malignant transformation. My laboratory focuses on understanding the cooperative interactions that conspire to transform human cells. To address this question, we have developed new experimental models of human cancer of defined genetic composition, created methods to perform systematic interrogation of gene function in mammalian cells and tissues and help optimize new approaches to integrate genome scale data. Using these approaches, we have identified and credential new oncogenes and tumor suppressor genes and have performed preclinical studies that will form the foundation necessary for translational studies in patients.
Specifically, we have developed genetic methods that permit the construction of genetically defined, experimental models of the major human epithelial cancers from primary human cells through the manipulation of oncogenes, tumor suppressor genes and telomerase. These model systems have permitted us to study the molecular interactions that lead to cancer. In addition, we have performed proof-of-principle experiments that such experimental models will prove useful in the discovery and validation of molecularly targeted therapies. Indeed, these experimental models have allowed us to investigate the mechanisms by which EGFR and other oncogenes and tumor suppressors contribute to cancer initiation. In particular, we have elucidated the role of the PP2A family of serine-threonine phosphatases as tumor suppressor genes.
As a Senior Associate Member of the Broad Institute, I lead efforts to apply functional genomic approaches to cancer. Specifically, I serve as one of the co-principal investigators for the RNAi Consortium (TRC), which has created a genome scale RNA interference library, and have established RNAi screening facilities at both the Broad Institute and the Dana-Farber Cancer Institute (DFCI). In my own laboratory, we are engaged in using these RNAi libraries to apply a comprehensive program to identify cancer vulnerabilities. Using these approaches, we have already discovered several new oncogenes including IKBKE, CDK8, CRKL, CDK6, and PAK1. I also co-direct the Center for Cancer Genome Discovery, which is committed to the development and implementation of technologies that permit the interrogation of cancer-associated mutations at genome scale and to implement these technologies prospectively in newly diagnosed patients.