Elucidating how nuclear FAK drives thyroid cancer progression and metastasis

项目总结/文摘

Project Summary/Abstract Late stage differentiated thyroid cancers characterized by metastasis and invasion have a poor prognosis compared to those with localized disease. However, there are limited therapeutic options and few biomarkers to indicate which patients will develop aggressive disease. To develop novel therapeutic targets and biomarkers, it is vital to understand tumor progression and metastasis in thyroid cancer. Environmental stressors such as hypoxia and oxidative stress have been shown to promote metastasis and interestingly thyroid cancer tissue has higher levels of DNA oxidative stress compared to normal thyroid tissue. It is not currently known how the oxidative stress environment of the thyroid contributes to thyroid cancer progression. Our lab has identified Focal Adhesion Kinase (FAK) as a key regulator of thyroid cancer growth, invasion, and metastasis. FAK is a non- receptor tyrosine kinase that localizes to the plasma membrane and becomes auto-phosphorylated at tyrosine 397 (Y397) in response to integrin or growth factor receptor signaling. In the context of cellular stress, FAK has been shown to localize to the nucleus via a nuclear localization sequence. We have found that FAK localizes to the nucleus in a subset of thyroid cancers but the mechanism of FAK nuclear localization and its role in tumor progression is not known. I have found that phosphorylation of FAK at Y397 is required for FAK translocation to the nucleus and that environmental stressors such as acquired drug resistance promote FAK translocation to the nucleus. Furthermore, I discovered that acquired drug resistance and oxidative stress increase anchorage independent growth and that excluding FAK from the nucleus or mutating the Y397 FAK site ablates anchorage independent growth. Taken together, this led me to hypothesize that oxidative stress promotes FAK localization to the nucleus through Y397 phosphorylation to drive tumor survival and metastasis. The goals of this proposal are to determine: 1) how FAK phosphorylation induces nuclear localization of FAK in the context of oxidative stress, 2) whether nuclear FAK promotes a metastatic phenotype through phosphorylation, and 3) if FAK expression, phosphorylation, and localization is correlated with tumor staging, mutational status, and disease recurrence in human thyroid tissue. The expected outcomes will identify a novel mechanism of how FAK localizes to the nucleus in response to oxidative stress and how FAK drives a metastatic phenotype through phosphorylation. These results will have a positive impact by identifying novel therapeutic targets and biomarkers in thyroid cancer.