Dr. Filippo Giancotti
The University of Texas MD Anderson Cancer Center
Department of Cancer Biology
Dominant mutations in oncogenes and recessive mutations in tumor suppressor genes disrupt the regulatory circuits that govern cells, endowing them with the ability to survive, proliferate, and invade independently of contextual constrains. Our laboratory studies the molecular basis of tumor initiation and progression to metastasis with emphasis on the role of adhesion signaling in these processes. We are currently examining four inter-related topics: 1) We are using mouse genetics and biochemistry to study the role of integrins — cell-matrix adhesion receptors — in tumor progression and metastasis. Our results indicate that integrin signals govern the self-renewal and invasive capacity of cancer stem cells. 2) We are studying the mechanisms by which the cadherins — cell-to-cell adhesion receptors — suppress cell proliferation. We have identified the tumor suppressor Merlin/NF2 as a critical mediator of contact inhibition of growth and demonstrated that inhibits cell proliferation by inhibiting the E3 ubiquitin ligase CRL4-DCAF1 in the nucleus. 3) We are studying the role of the Epithelial-to-Mesenchymal Transformation (EMT) and the reverse process (MET) in self-renewal and metastatic colonization. 4) Early dissemination of tumor cells followed by an extended period of proliferative quiescence is thought to explain late relapse in breast cancer and other cancers. We are using forward genetic screens in the mouse to identify the signaling, transcriptional, and epigenetic mechanisms that govern metastatic dormancy and reactivation in breast, prostate, and pancreatic cancer. By delineating new mechanisms underlying tumor initiation and progression to metastasis, we hope to identify novel targets for therapeutic intervention.