The overall goal of this proposal is to understand the role of focal adhesion kinase (FAK) in promoting tumor progression. Work from a number of labs has identified FAK as an important intracellular tyrosine kinase activated by integrins and growth factor receptors. In many advanced and metastatic tumors, FAK is over-expressed, catalytically-active, and highly tyrosine phosphorylated. FAK is activated also in tumor-associated endothelial cells (ECs). Although a small molecule inhibitor to FAK has anti-tumor activity, targets of inhibitor action between tumor or stromal cells remain unclear. In the last funding period, we showed that FAK catalytic activity within breast carcinoma cells enhances tumor growth and metastasis by promoting protease and vascular endothelial growth factor expression. Here, we will build upon these studies and will test whether the inhibition of FAK activity selectively within tumor cells, stromal ECs, or both will affect breast or ovarian carcinoma tumor progression. Our proposal will combine genetic (shRNA knockdown and FAK or FAK-related kinase Pyk2 re-expression), pharmacological (small molecular inhibitors to FAK and/or FAK/Pyk2), and syngeneic mouse models incorporating a kinase-dead FAK knock-in mutation and the inducible conditional knockout of FAK within ECs, i-EC-FAK-KO.
Aims 1 and 2 will determine whether blocking FAK signaling in tumor or stroma will affect either tumor growth or spontaneous metastasis after orthotopic implantation of breast or ovarian carcinoma cells in a native microenvironment within fully immune-competent mice. These studies will be the first to test the role of FAK signaling within ECs as a potential contributor to tumor progression.
Aim -3 will build upon studies where we found that FAK can promote cell survival through a novel FAK kinase-independent mechanism involving FAK nuclear localization in preventing p53 tumor suppressor- mediated cell apoptosis. We will test whether nuclear targeting and p53 binding properties of the FAK amino-terminal FERM domain are shared between FAK and Pyk2, and whether FAK can function in a kinase-independent manner to promote p53 wildtype ovarian carcinoma tumor progression through alterations in cell survival or increased resistance to cisplatin.
This aim will yield key information on potential differences of FAK as an adaptor protein compared to FAK as signaling kinase. Completion of these aims will yield important insights into FAK function and will aid in the development of strategies to control the growth and spread of tumor cells.
Tumor cells do not progress to malignancy in isolation - the microenvironment of the tumor can either enhance or suppress tumor growth and progression. We are investigating the molecular mechanism of how focal adhesion kinase (FAK) signaling facilitates tumor progression through both kinase-dependent and independent mechanisms influencing the tumor microenvironment. These studies will fill key gaps in our understanding of integrin-associated signaling events regulating tumor growth and spread.
|Kleinschmidt, Elizabeth G; Schlaepfer, David D (2017) Focal adhesion kinase signaling in unexpected places. Curr Opin Cell Biol 45:24-30|
|Delaney, Joe Ryan; Patel, Chandni B; Willis, Katelyn McCabe et al. (2017) Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer. Nat Commun 8:14423|
|Laklai, Hanane; Miroshnikova, Yekaterina A; Pickup, Michael W et al. (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22:497-505|
|Yurdagul Jr, Arif; Sulzmaier, Florian J; Chen, Xiao L et al. (2016) Oxidized LDL induces FAK-dependent RSK signaling to drive NF-?B activation and VCAM-1 expression. J Cell Sci 129:1580-91|
|Masià-Balagué, Miriam; Izquierdo, Ismael; Garrido, Georgina et al. (2015) Gastrin-stimulated G?13 Activation of Rgnef Protein (ArhGEF28) in DLD-1 Colon Carcinoma Cells. J Biol Chem 290:15197-209|
|Young, Shanique A; McCabe, Katelyn E; Bartakova, Alena et al. (2015) Integrin ?4 Enhances Metastasis and May Be Associated with Poor Prognosis in MYCN-low Neuroblastoma. PLoS One 10:e0120815|
|Gao, Chenxi; Chen, Guangming; Kuan, Shih-Fan et al. (2015) FAK/PYK2 promotes the Wnt/?-catenin pathway and intestinal tumorigenesis by phosphorylating GSK3?. Elife 4:|
|Tancioni, Isabelle; Miller, Nichol L G; Uryu, Sean et al. (2015) FAK activity protects nucleostemin in facilitating breast cancer spheroid and tumor growth. Breast Cancer Res 17:47|
|Delaney, Joe R; Patel, Chandni; McCabe, Katelyn E et al. (2015) A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer. Oncotarget 6:31104-18|
|Tancioni, Isabelle; Uryu, Sean; Sulzmaier, Florian J et al. (2014) FAK Inhibition disrupts a ?5 integrin signaling axis controlling anchorage-independent ovarian carcinoma growth. Mol Cancer Ther 13:2050-61|
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