Effects of Microenvironmental Stiffness on Epigenetic Regulation

微环境硬度对表观遗传调控的影响

• 批准号: 9326877
• 负责人: Ryan Stowers
• 金额: $ 5.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9326877
• 关键词: Acinus organ component; Automobile Driving; Behavior; Binding; Biological Assay; Breast Cancer Cell; Breast Epithelial Cells; Cancer Etiology; Cause of Death; Cell Count; Cells; Cessation of life; Chromatin; Cultured Cells; Data; Disease Progression; Environment; Epigenetic Process; Gel; Gene Expression; Goals; Growth; Heritability; Hydrogels; In Vitro; Invaded; Knowledge; Left; Ligands; MCF10A cells; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mechanics; Memory; Modification; Molecular; Neoplasm Metastasis; Non-Malignant; Outcome; Patient-Focused Outcomes; Phenotype; Prevention strategy; Primary Neoplasm; Property; RNA Interference; Research; Testing; Time; Work; base; cancer cell; cell growth; chromatin remodeling; density; driving force; epigenetic regulation; epigenomics; experimental study; genome-wide; improved; in vitro Model; malignant breast neoplasm; malignant phenotype; mammary epithelium; mechanical properties; new therapeutic target; novel; novel therapeutics; prevent; response; small molecule; soft tissue; three dimensional cell culture; three-dimensional modeling; trait; transcription factor; treatment strategy; tumor; tumor microenvironment; tumor progression

Tumor stiffness has been implicated as a driving force in tumor progression and metastasis. Matrix stiffness has been shown to alter the phenotype of breast epithelial cells from growth-arrested in soft conditions to malignant and invasive in stiff conditions. However, it is unknown whether invading cells retain `memory' of stiff environments after dissemination from the primary tumor, and if so, by what mechanism. This proposal aims to determine the extent and basis of mechanical memory of stiff microenvironments in mammary epithelial cells. Using a novel 3D model in which matrix stiffness can be tuned independently of ligand density, polarized, growth arrested mammary acini can be generated in soft gels while stiff gels give rise to malignant, invasive phenotypes. After culture in either soft or stiff conditions, the gel stiffness will be altered to determine the reversibility of the phenotypes initially established. These experiments will demonstrate whether mechanical memory exists for breast epithelial cells or in cancer contexts in general. Next chromatin accessibility and transcription factor occupancy will be assessed genome-wide using a transposition-based assay (ATAC-seq) suited for low cells numbers required for 3D culture. Epigenetic modifiers will be screened based on candidates identified from epigenomic data to identify the molecular mechanism driving stiffness-induced chromatin remodeling. Successful completion of this proposal will reveal, for the first time, the extent of mechanical memory in a cancer context, and the epigenomic landscape of cells in 3D culture.

肿瘤僵硬已被认为是肿瘤进展和转移的驱动力。刚度矩阵