The long term goal of this proposal is to understand how growth promoting and restricting signals interact to balance one another and how their deregulation leads to the development of neoplastic tumors which often turn into malignant, metastatic carcinomas. My preliminary data revealed that loss of TGF-p receptor II (T(3RII) function in the skin epithelium produces spontaneous anal and genital squamous cell carcinomas (SCCs) and cooperates with active H-Ras to form metastatic SCCs. Focal adhesion kinase (FAK) mediated integrin signaling is hyperactive in these carcinomas and cultured keratinocytes suggesting a direct link between TfiRII loss and FAK activation. Indeed, FAK has been reported to be the most commonly hyper- activated non receptor tyrosine kinase in epithelial tumors and tumor cell lines, yet its functions and molecular targets are largely unknown. The central hypothesis tested by this proposal is that FAK plays a central role in the development of SCCs in TpRII deficient skin epithelium. This hypothesis will be tested experimentally by: 1) assessing the probabilities to develop spontaneous anal and genital, or chemically induced SCCs in skin of WT, JftRII and FAK single and TJ3RII/FAK double conditional mutant mice and investigating the underlying cellular and pathological alterations;3) investigate how loss of TpRII and increased FAK activity promote skin carcinogenesis, malignant progression, and invasive metastatic keratinocyte migration;and 2) identification of molecular mechanisms by which loss of TfSRIlfunction in keratinocytes promotes FAK activation. Data generated from the proposed experiments will advance our understanding of the molecular functions of TPRII and FAK mediated integrin signaling in normal development and disease, identify the molecular mechanisms by which growth promoting Ras and Integrin signaling interact with growth restricting TGF-P signaling to control not only proliferation, but also cell survival, cytoskeletal dynamics and invasive cell migration, and identify novel molecular pathways by which carcinomas form even in the absence of FAK function. Together, this proposal will strengthen our molecular and cellular understanding of carcinogenesis and will reveal potential therapeutic targets.
|Siegle, Jasmin M; Basin, Alice; Sastre-Perona, Ana et al. (2014) SOX2 is a cancer-specific regulator of tumour initiating potential in cutaneous squamous cell carcinoma. Nat Commun 5:4511|
|Schober, Markus; Fuchs, Elaine (2011) Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-ýý and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci U S A 108:10544-9|