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

机械应激重新编程线粒体代谢，通过线粒体未折叠蛋白反应支持肿瘤存活和侵袭

• 批准号: 9985586
• 负责人: Kevin Tharp
• 金额: $ 4.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9985586
• 关键词: Actomyosin; Adhesions; Aggressive behavior; Aging; Atomic Force Microscopy; Behavior; Biomedical Engineering; Brain Neoplasms; Breast Cancer Model; Breast Epithelial Cells; Cancerous; Carcinoma; Cells; Characteristics; Coupled; Cytoskeleton; Data; Deposition; Disease; Elasticity; Electron Transport; Electrons; Etiology; Extracellular Matrix; Feedback; Fostering; Gene Expression; Genetic; Genetic Transcription; HSF1; Image; Integrins; Learning; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mechanical Stress; Mechanics; Mediating; Mentors; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Neoplasm Metastasis; Normal tissue morphology; Oxidants; Oxidation-Reduction; Oxygen; Pharmacology; Proteins; Research; Role; Signal Transduction; Solid Neoplasm; Stress; Structure; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Treatment Protocols; anti-cancer therapeutic; biological adaptation to stress; cancer therapy; career; cell behavior; combat; crosslink; effective intervention; genetic manipulation; in vivo; knock-down; mammary epithelium; mechanical force; mitochondrial metabolism; neoplastic cell; novel therapeutic intervention; polyacrylamide hydrogels; premalignant; programs; response; small hairpin RNA; therapeutic target; training opportunity; tumor; tumor microenvironment; tumor progression; two-dimensional

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.

项目摘要 异常的代谢和物理特征是肿瘤的最显著特征， 回到它们的组织来源。我提出的研究计划将从分子上定义机械应力如何改变 线粒体代谢来支持转移性疾病。我的初步数据显示，遗传和外源性 机械应力可以通过诱导线粒体内的线粒体蛋白质， 未折叠蛋白反应（UPRmt），其诱导已知在转移性肿瘤中富集的适应。 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，同时也解释了癌症的相互联系。 癌组织的机械和代谢异常。 我将使用简化的二维ECM官能化聚丙烯酰胺水凝胶（PA-凝胶）， 概括“正常”组织间质（400 Pa），癌前和早期浸润促进间质（6 kPa）和高度刚性的肿瘤基质（60 kPa），以评估ECM刚度对线粒体的影响。 代谢，氧化还原信号传导和癌症相关的适应性应激反应（由HSF 1介导的UPRmt和 ATF 5）。在这些机械应力模型中，我将定义HSF 1和ATF 5的作用，线粒体结构， 转换，整合素信号转导（通过遗传学和药理学方法）和肌动球蛋白 介导的收缩力（通过遗传和药理学方法）。然后我会询问 对肿瘤微环境的机械信号的反应需要HSF 1和ATF 5来处理恶性肿瘤。 行为使用乳腺肿瘤模型开发的韦弗实验室。 总之，目标1：表征响应于机械刺激而发生的线粒体变化。 应力目的2：确定线粒体活性氧信号是否触发适应性应激反应， 转移性细胞骨架动力学目的3：测试由以下物质催化的乳腺肿瘤的存活力和侵袭力： 机械应力通过HSF 1和ATF 5介导的线粒体诱导的UPRmt来处理。 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， 我和我的导师认为这些概念是重要的体验式培训机会， 我的独立研究生涯。