Role of Sox2 in Stress Adaptations to Ovarian Cancer Anchorage Independence

项目总结 晚期卵巢癌的特点是由于腹膜腔内的转移扩散，患者存活率较低。 腹膜恶性腹水中的肿瘤细胞表现出对锚定非依赖生存的适应性 是跨体腔转移所必需的。因此，定义支持锚定的关键适应信号 腹水中的独立存活将导致控制卵巢癌相关死亡率的新方法。 我们最近发现了Sox2，一个关键的发育基因，作为锚定非依赖性的重要调节因子 生死存亡。SOX2在癌症干细胞中的作用先前的报道强调了SOX2在癌症中的S意义 以及与病人存活率差的关联。奇怪的是，近75%的卵巢肿瘤显示出SOX2基因 拷贝数增加，SOX2在肿瘤中的表达与SOX2扩增无关。它的意义 因此，SOX2扩增与卵巢癌进展的病因学的关系仍然难以捉摸。我们现在发现， SOX2在卵巢癌中以上下文依赖的方式显著升高，在失去依恋和 对于独立于锚地的生存来说是必要的。我们已经确定了Sox2以前未曾探索过的功能 线粒体功能的主要调节者，在锚定独立性中重要的生存适应。SOX2 促进线粒体呼吸和线粒体电子传递链所需基因的表达 转录和翻译，以及抗氧化功能，包括锰超氧化物歧化酶，Sod2。 而Sox2的S最确立的角色是在开发过程中的世系规范，SOX2通过哪些机制 在卵巢癌中被调控，并在转移过程中促进生存在很大程度上是未知的。因此，我们的目标是 这里将SOX2定义为线粒体控制的应激反应通路的汇聚点 采用体外和体内相结合的方法进行卵巢癌转移。要实现这些目标 目标，我们将：1)在表观遗传学的背景下定义锚定独立条件下Sox2的调节 与丧失依恋有关的调节、代谢和氧化还原应激；2)通过 哪一种Sox2是线粒体功能和质量控制的关键调节因子；以及3)决定必要性 SOX2驱动的线粒体功能对锚定非依赖性生存和转移的影响。我们的研究将 为SOX2在卵巢癌中的动态调控和作用提供有意义的新知识。定义 SOX2-线粒体轴是卵巢癌锚定非依赖性生存和转移的关键适应因素 将是确定卵巢癌关键的应激适应的重要一步，可以作为治疗的靶点。

PROJECT SUMMARY Late stage ovarian cancer is marked by poor patient survival due to metastatic spread in the peritoneal cavity. Malignant ascites in the peritoneum harbor tumor cells that exhibit adaptability to anchorage independent survival required for transcoelomic metastasis. Thus, defining key adaptation signals that support anchorage independent survival in the ascites will result in new approaches to control ovarian cancer associated mortality. We recently uncovered Sox2, a key developmental gene, as an important regulator of anchorage independent survival. Sox2’s significance in cancer is underscored by prior reports on Sox2 functions in cancer stem cells and associations with poor patient survival. Curiously, while close to 75% of ovarian tumors display SOX2 gene copy number gain, Sox2 expression does not correlate with this SOX2 amplification in tumors. The significance of SOX2 amplification to the etiology of ovarian cancer progression hence remains elusive. We now find that Sox2 is significantly elevated in a context-dependent manner in ovarian cancer upon loss of attachment and necessary for anchorage-independent survival. We have identified a previously unexplored function of Sox2 as a master regulator of mitochondrial function, an important survival adaptation in anchorage independence. Sox2 promotes mitochondrial respiration and expression of genes required for mitochondrial electron transport chain transcription and translation, and antioxidant function, including the manganese superoxide dismutase, Sod2. While Sox2’s most established role is in lineage specification during development, mechanisms by which Sox2 is regulated in ovarian cancer and promotes survival during metastasis are largely unknown. Thus, our objectives here are to define Sox2 as a convergence point of stress response pathways for mitochondrial control during ovarian cancer metastasis using a combination of in vitro and in vivo approaches. To accomplish these objectives, we will: 1) Define regulation of Sox2 under anchorage independence in the context of epigenetic regulation and metabolic and redox stress associated with loss of attachment; 2) Delineate the mechanisms by which Sox2 acts as a key regulator of mitochondrial function and quality control; and 3) Determine the necessity of Sox2-driven mitochondrial function for anchorage independent survival and metastasis. Our studies will provide significant new knowledge on the dynamic regulation and role of Sox2 in ovarian cancer. Defining the Sox2-mitochondrial axis as a key adaptation for ovarian cancer anchorage-independent survival and metastasis will be a major step in identifying key stress adaptations of ovarian cancer that can be targeted therapeutically.