MERIT Award Recipient: Filippo G. Giancotti, M.D., Ph.D.
Molecular Analysis of the alpha-6 beta-4 Integrin
The integrin receptors attach cells to the extracellular matrix and transmit mechanical and chemical signals to the cell interior. Certain integrins are able to cooperate with growth factor receptors to activate signaling pathways necessary for cell proliferation, whereas other integrins are not able to do so or even deliver inhibitory signals. In a similar fashion, integrin-specific signals dictate whether adhesion to the matrix promotes cell survival or apoptotic cell death and stable adhesion or cell migration. Dominant mutations in oncogenes and recessive mutations in tumor suppressor genes enable neoplastic cells to survive, proliferate, and migrate independently of the positional constrains operating on normal cells. It is increasingly clear that the upregulation of integrins that promote cell survival, proliferation, and migration and the downregulation of integrins that mediate stable adhesion play a key role in tumor invasion and metastasis.
A major objective of the Giancotti Laboratory is to understand at the molecular level the mechanisms by which individual integrins promote or suppress tumor invasion and metastasis. In this context, the laboratory is also interested in the role that integrin signaling plays in tumor angiogenesis. The MERIT Award honors the efforts of the laboratory in the study of the alpha-6 beta-4 integrin. Strong evidence suggests that alpha-6 beta-4 promotes epithelial and endothelial cell proliferation and migration and that it may play a pivotal role in carcinoma invasion.
The Giancotti Laboratory uses a two-pronged strategy to examine the role of alpha-6 beta-4 in tumor invasion and metastasis. First, cell biological and biochemical methods are used to elucidate the mechanisms by which alpha-6 beta-4 cooperates with activated growth factor receptors to promote cell proliferation and migration/invasion. Emphasis is placed on the role of Src family kinases and Rho proteins. Second, mouse molecular genetics methods are employed to examine the role of alpha-6 beta-4 signaling in tumor invasion and angiogenesis in vivo. The laboratory has generated mice carrying a targeted deletion of the signaling domain of beta-4. This mutation has then been introduced in mice carrying certain dominant oncogenes or lacking certain tumor suppressor genes. This approach is enabling the laboratory to assess the impact of alpha-6 beta-4 signaling on tumor progression and metastasis in various organs, including skin, breast, thyroid, and prostate. These studies should provide a rational basis to future efforts to develop alpha-6 beta-4 inhibitors for cancer therapy.