Oncogenic mutations disrupt the regulatory circuits that govern the behavior of cells, endowing them with the ability to survive, proliferate and invade independently of contextual constrains imposed by their immediate microenvironment. Upon dissemination and seeding of target organs, tumor cells must evade initial attrition and resume their expansion to give rise to metastatic lesions. Our laboratory studies the molecular basis of tumor initiation and progression to metastasis with emphasis on the role of cell adhesion and signaling. Our areas of research include:
- Integrin signaling
- Epithelial-to-Mesenchymal Transition
- Cancer stem cells
- Metastatic dormancy and reactivation
- Resistance to therapy
The integrins are a large class of cell adhesion receptors, and many of them are involved in adhesion to the extracellular matrix. We have contributed to the identification of key integrin signaling mechanisms and the realization that, although integrin signaling is extremely complex and yet specific, its logic is elegantly simple: certain integrins buttress mitogenic and pro-survival signaling by receptor tyrosine kinases, whereas others do not exert this effect or even inhibit mitogenic signaling. Through careful genetic analysis in vivo and biochemical analysis in culture, we have provided evidence that integrin signaling contributes to breast and prostate tumorigenesis. We're currently studying the mechanisms through which integrin signaling governs the self-renewal and invasive capacity of cancer stem cells.
In subsequent and more recent work, we have demonstrated that Merlin, which is encoded by the NF2 tumor suppressor gene, mediates contact inhibition of proliferation and suppresses tumorigenesis by entering the nucleus to inhibit the E3 ubiquitin ligase CRL4DCAF1. This ligase in turn represses the function of the Hippo pathway component Lats. In the short span of a few years, our group has elucidated a major mechanism through which Merlin suppresses tumorigenesis - a process that has remained mysterious since the discovery of the NF2 gene in 1993. We're currently examining the relative roles of cortical and nuclear Merlin in contact inhibition and tumor suppression based on the alternative complexes that in which the protein participates at the two locations.
A major component of our research program focuses on metastatic dissemination and colonization. We have identified oncogenic alterations that drive the Epithelial-to-Mesenchymal Transformation and dissemination in breast and prostate cancer. Furthermore, we have developed powerful gain-of-function genetic screens that enable the identification of mediators of metastatic reactivation. By using this approach, we have begun to identify the major signaling pathways that trigger metastatic reactivation. Our most recent findings indicate that the metastasis-initiating cells undergo dormancy and reactivation in response to signaling pathways similar to those that govern these processes in adult stem cells, including niche signals organized by the matrix.
Our research program spans several cancer types - including breast, prostate and pancreatic cancer - and multiple target organs, and it aims to not only shed light on the biology of the most mysterious phase of metastasis but also to bring to the clinic an entire new class of therapeutics.