Filippo Giancotti: Projects

Complexity and Specificity of Integrin Signaling

Certain integrins cooperate with Receptor Tyrosine Kinases (RTKs) to promote cell survival, cell proliferation, and cell migration. Other integrins do not exert this effect, and some even oppose the action of RTKs. We are studying the mechanisms by which the integrins exert these effects.

Integrin β4 Signaling in Cancer

The β4 integrin is characterized by a unique cytoplasmic domain and plays a key role in tumorigenesis. We are elucidating the mechanisms by which β4 amplifies the signaling capacity of oncogenic receptor tyrosine kinases, such as ErbB2 and Met, in breast and prostate cancer.

Focal Adhesion Kinase Signaling in Tumorigenesis

FAK is activated by all integrins with the possible exception of β4 and is therefore considered a core component in integrin signaling. Notably, inactivation of FAK blocks tumor initiation and inhibits progression to metastasis in a mouse model of mammary tumorigenesis driven by activation of PI-3K. In addition, deletion of FAK induces growth arrest and apoptosis in human breast cancer cells carrying various prevalent oncogenic mutations. We are dissecting the molecular mechanisms by which FAK exerts these profound effects on mammary tumorigenesis.

Contact Inhibition and Merlin

The tumor suppressor Merlin, which is inactivated in Schwannomas and malignant mesotheliomas, play a key role in contact-mediated inhibition of growth. We have discovered that Merlin suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4DCAF1 in the nucleus. We are using mouse genetics and biochemistry to study this novel tumor suppressor pathway.

Epithelial-to-Mesenchymal Transition (EMT) in Cancer

Certain oncogenic mutations induce tumor cells to hijack a developmental program of gene expression, the Epithelial to Mesenchymal Transition (EMT), in order to gain invasive capacity. We are studying two novel tumor suppressor proteins that exert their function predominantly by antagonizing the EMT.

Tumor Dormancy and Reactivation at Metastatic Sites

Metastatic relapse of breast cancer and other tumor types usually occurs several years after surgical resection of the primary tumor. Early dissemination of tumor cells followed by an extended period of dormancy is thought to explain this prevalent clinical behavior. We are using a gain-of-function retroviral cDNA screen in the mouse to identify genes that induce solitary carcinoma cells to exit from dormancy at lung and bone metastatic sites.