Mechanical stress reprograms mitochondrial metabolism to support tumor survival and invasion through the mitochondrial unfolded protein response

项目摘要 相比较而言，异常的代谢和生理特征是肿瘤最显著的特征 它们的起源组织。我提议的研究计划将从分子上定义机械应力如何改变 支持转移性疾病的线粒体代谢。我的初步数据显示，基因和外源 机械应激可通过诱导线粒体对乳腺上皮细胞进行代谢重新编程 未折叠蛋白反应(UPRmt)，它诱导已知在转移肿瘤中丰富的适应性。 阐明细胞力学、线粒体信号和适应性应激反应之间的关系 可能会发现不可预见的癌症治疗机会，同时也解释了 癌组织的机械和代谢异常。 我将使用简化的二维ECM功能化聚丙烯酰胺水凝胶(PA-Gel) 概述“正常”组织间质(400pa)、癌前和早期侵袭促进间质(6 Kpa)和高硬度的肿瘤间质(60kpa)，以评估细胞外基质僵硬对线粒体的影响 代谢、氧化还原信号和癌症相关的适应性应激反应(由HSF1和UPRmt介导) ATF5)。在这些机械应力模型中，我将定义HSF1和ATF5在线粒体结构中的作用 转化、整合素信号转导(通过遗传和药理学方法)和肌动球蛋白 调节的收缩能力(通过遗传和药理学方法)。然后我会询问手机是否 对肿瘤微环境机械信号的反应需要HSF1和ATF5来处理恶性 使用韦弗实验室开发的乳腺肿瘤模型的行为。 总而言之，目标1：描述机械反应中发生的线粒体变化 压力。目的2：确定线粒体活性氧信号是否触发适应性应激反应和 转移性细胞骨架动力学。目的3：检测黄曲霉毒素对乳腺肿瘤的活性和侵袭力 机械应力是通过线粒体诱导的HSF1和ATF5介导的UPRmt来处理的 氧化剂信号。此外，为了完成这个项目，我将学习和使用实验技术和 我和我的导师认为这些概念是重要的体验式培训机会，将 成就了我的独立研究事业。

Project Summary Aberrant metabolic and physical characteristics are the most salient features of tumors when compared to their tissue of origin. My proposed research program will molecularly define how mechanical stresses alter mitochondrial metabolism to support metastatic disease. My preliminary data show that genetic and exogenous mechanical stress can metabolically reprogram mammary epithelial cells by inducing the mitochondrial unfolded protein response (UPRmt) which induces adaptations known to be enriched in metastatic tumors. Clarifying the relationship between cellular mechanics, mitochondrial signals, and adaptive stress responses may uncover unforeseen cancer treatment opportunities while also explaining the interconnectedness of the mechanical and metabolic abnormalities of cancerous tissues. I will use simplified two dimensional ECM functionalized polyacrylamide hydrogels (PA-gels) that recapitulate the “normal” tissue stroma (400 Pa), the premalignant and early invasive promoting stroma (6 kPa), and the highly rigid tumor stroma (60 kPa) to assess the impact of ECM stiffness on mitochondrial metabolism, redox signaling, and cancer associated adaptive stress responses (UPRmt mediated by HSF1 and ATF5). In these models of mechanical stress, I will define the roles of HSF1 and ATF5, mitochondrial structural transitions, integrin signal transduction (via genetic and pharmacological approaches), and actomyosin mediated contractility (via genetic and pharmacological approaches). I will then interrogate if the cellular responses to mechanical signals of the tumor microenvironment require HSF1 and ATF5 to dispose malignant behavior using mammary tumor models developed in the Weaver lab. In summary, Aim 1: Characterize the mitochondrial changes that occur in response to mechanical stress. Aim 2: Determine if mitochondrial reactive oxygen signals trigger adaptive stress responses and metastatic cytoskeletal dynamics. Aim 3: Test if viability and invasiveness of mammary tumors catalyzed by mechanical stresses is disposed through an HSF1- and ATF5-mediated UPRmt induced by mitochondrial oxidant signals. Additionally, to accomplish this project I will learn and use experimental techniques and concepts that my mentors and I have identified as important experiential training opportunities that will engender my independent research career.