Elucidating how nuclear FAK drives thyroid cancer progression and metastasis

项目总结/摘要 晚期分化型甲状腺癌以转移和浸润为特征，预后差 与那些患有局部疾病的人相比。然而，治疗选择有限，生物标志物也很少， 表明哪些患者将发展为侵袭性疾病。为了开发新的治疗靶点和生物标志物， 对了解甲状腺癌的进展和转移至关重要。环境压力，如 缺氧和氧化应激已经显示出促进转移，有趣的是甲状腺癌组织已经 与正常甲状腺组织相比，DNA氧化应激水平较高。目前尚不清楚， 甲状腺的氧化应激环境有助于甲状腺癌的进展。我们的实验室已经鉴定出 粘附激酶（FAK）是甲状腺癌生长、侵袭和转移的关键调节因子。FAK是一个非- 一种受体酪氨酸激酶，定位于质膜并在酪氨酸 397（Y397），其响应于整联蛋白或生长因子受体信号传导。在细胞应激的背景下，FAK具有 已被证明通过核定位序列定位于细胞核。我们发现FAK定位于 但FAK的核定位机制及其在肿瘤中的作用 进展尚不清楚。我已经发现FAK在Y397的磷酸化是FAK易位到 细胞核和环境应激因子如获得性耐药性促进FAK易位， 原子核此外，我发现获得性耐药性和氧化应激增加锚定 将FAK从细胞核中排除或突变Y397 FAK位点消除锚定 独立成长。综上所述，这使我假设氧化应激促进FAK 通过Y397磷酸化定位到细胞核以驱动肿瘤存活和转移。 该建议的目标是确定：1）FAK磷酸化如何诱导FAK在细胞核中的定位， 氧化应激的背景下，2）核FAK是否促进转移表型， 3）如果FAK表达、磷酸化和定位与肿瘤分期相关， 突变状态和疾病复发。预期的结果将确定一个新的 FAK如何响应于氧化应激定位于细胞核以及FAK如何驱动转移性肿瘤的机制 表型通过磷酸化。这些结果将产生积极的影响，通过确定新的治疗方法， 甲状腺癌的靶点和生物标志物。

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.