Fibrotic extracellular matrix: uncovering its role in breast cancer genome stability and metabolic plasticity

纤维化细胞外基质：揭示其在乳腺癌基因组稳定性和代谢可塑性中的作用

• 批准号: 10507566
• 负责人: Elizabeth S Moore
• 金额: $ 11.02万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507566
• 关键词: 3-Dimensional; Activation Analysis; Antineoplastic Agents; Antioxidants; Basal Cell Cancer; Basal metabolic rate; Biologic Characteristic; Biological Assay; Biological Markers; Biological Models; Biological Sciences; Biophysics; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer Treatment; Breast Cancer cell line; Breast Cancer therapy; Cancer Biology; Cancer Prognosis; Cell Communication; Cell Cycle Checkpoint; Cellular Metabolic Process; Chromatin; Clinical; Collagen; Collagen Type I; Complement; Core Facility; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA crosslink; Data; Deposition; Detection; Drug resistance; Educational process of instructing; Engineering; Environment; Extracellular Matrix; Faculty; Fiber; Fibrillar Collagen; Fibrosis; Future; Gene Expression Profiling; Genetic; Genetic Transcription; Genome Stability; Genus Hippocampus; Goals; Grant; Growth; Human; Image; Immunofluorescence Immunologic; In Vitro; Kinetics; Knowledge; Laboratories; Laboratory Animal Medicine; Link; Mammary Neoplasms; Manuscripts; Mediating; Mentored Research Scientist Development Award; Mentors; Mentorship; Metabolic; Metabolism; Methodology; Molecular; Molecular Genetics; Mus; Mutagens; Oncology; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Pharmacotherapy; Phenotype; Phosphotransferases; Plasmids; Play; Preparation; Process; Property; Regulation; Reporter; Reporting; Research; Research Training; Resistance; Resolution; Role; Scientist; Signal Transduction; Stromal Cells; Structure; Surgical Models; System; Technical Expertise; Techniques; Testing; Therapeutic; Tissue Engineering; Training; Universities; animal model development; base; cancer drug resistance; cancer therapy; career; career development; chemotherapeutic agent; chemotherapy; clinical care; clinical prognosis; experience; extracellular; fatty acid oxidation; humanized mouse; improved; in vivo; in vivo Model; innovation; interdisciplinary approach; interdisciplinary collaboration; malignant breast neoplasm; mammary; mechanical properties; metabolic phenotype; metabolomics; mouse model; neoplastic cell; novel; patient derived xenograft model; patient prognosis; physical science; programs; recruit; repaired; replication stress; resistance mechanism; response; skills; symposium; therapy resistant; tissue culture; transcriptome sequencing; translational physician; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor metabolism; tumor microenvironment; tumor progression; tumorigenic

PROJECT ABSTRACT The candidate, Dr. Elizabeth Moore, seeks the proposed Mentored Research Scientist Development Award (K01) to acquire the necessary training and experience to become an independent translational clinician- scientist focusing on tumor microenvironmental regulation of breast cancer (BC) genome stability and therapeutic resistance. BC therapeutic resistance remains a major hindrance to successful treatment, particularly in the aggressive triple negative (TNBC) subtype. However, it remains unclear how therapeutic response is influenced by the physical and biological characteristics of the tumor microenvironment and which role altered DNA damage response (DDR) mechanisms and metabolic reprogramming play this process. In particular, it remains to be elucidated how fibrotic remodeling of the extracellular matrix (ECM), which is a hallmark feature of a protumorigenic microenvironment, impact BC risk and drug resistance. Given these connections, the overall objective of the proposed studies will be to identify mechanisms of matrix-mediated BC therapeutic resistance. Aim 1 will determine the impact of fibrotic ECM on BC DNA damage response (DDR). Aim 2 will test how fibrotic ECM regulates the DDR and metabolism of tumor cells and their reciprocal interactions. Aim 3 will test the functional links between fibrotic ECM, DDR, and metabolism in vivo. Aims 1 and 2 will utilize translationally relevant, high fidelity 3D tissue culture systems in which features of fibrotic ECM remodeling can be selectively adjusted. Aim 3 will leverage a humanized mouse model of mammary fibrosis and TNBC using human BC cell lines and patient derived xenografts of TNBC. A multidisciplinary approach, including classic molecular techniques, gene expression analyses, metabolomics and Seahorse metabolic analyses, and advanced imaging will be applied to achieve these aims and for the candidate to acquire additional technical skills. Dr. Moore’s mentor is a leading expert in engineering in vitro and in vivo models to study tumor-microenvironment interactions. Co-mentors will provide expertise in the fields of genome stability and the DDR, cellular metabolism and metabolomics, and clinical aspects of breast cancer. Faculty expertise and interdisciplinary collaboration in oncology research is exceptionally strong at Cornell University and further strengthened by the training environment and exceptional core facilities. The planned career development activities, including technical research training, coursework, attendance of seminars and conferences, experience in grant and manuscript preparation, and the refinement of teaching, mentorship, and laboratory management skills will support Dr. Moore’s transition to independence. The incorporation of physical and life science approaches, utilization of highly translational in vitro and in vivo platforms, and the integration of both extracellular and intracellular regulation of BC genome stability will enable Dr. Moore to establish a niche in oncology research. Proposed activities will generate data for a future R01 application and launch Dr. Moore’s faculty career in advancing the field of breast cancer biology with the goal to improve patient prognosis.

项目摘要 候选人伊丽莎白·摩尔博士寻求拟议的导师研究科学家发展奖 (K01)获取所需的训练和经验，以成为一名独立的翻译临床医生- 专注于乳腺癌(BC)基因组稳定性和肿瘤微环境调控的科学家 治疗抵抗力。BC治疗耐药性仍然是成功治疗的主要障碍， 尤其是侵袭性三阴性(TNBC)亚型。然而，目前还不清楚治疗效果如何。 反应受肿瘤微环境的物理和生物学特性的影响， 作用改变的DNA损伤反应(DDR)机制和代谢重编程在这一过程中发挥作用。在……里面 特别是，细胞外基质(ECM)的纤维化重塑如何仍有待阐明，ECM是一种 促癌微环境的显著特征，影响BC风险和耐药性。考虑到这些 联系，拟议研究的总体目标将是确定基质介导的机制 BC治疗耐药。目的1确定纤维化细胞外基质对BC DNA损伤反应的影响 (解甲返乡)。目标2将测试纤维化的ECM如何调节肿瘤细胞的DDR和代谢以及它们之间的相互作用 互动。目的3将测试纤维化ECM、DDR和体内新陈代谢之间的功能联系。目标1和 2将利用翻译相关的高保真3D组织培养系统，在该系统中纤维化的ECM的特征 改建可以有选择地进行调整。Aim 3将利用人源化的乳腺纤维化小鼠模型 使用人BC细胞系和患者来源的TNBC异种移植。一个多学科的方法， 包括经典的分子技术、基因表达分析、代谢组学和海马代谢 分析，并将应用先进的成像技术来实现这些目标，并让候选人获得 额外的技术技能。摩尔博士的导师是在体外和体内模型工程方面的领先专家 研究肿瘤与微环境的相互作用。合作导师将提供基因组稳定性领域的专业知识 以及乳腺癌的DDR、细胞代谢和代谢组学以及临床方面。教师专业知识 康奈尔大学在肿瘤学研究方面的跨学科合作格外强大，而且 由于培训环境和特殊的核心设施而得到加强。有计划的职业发展 活动，包括技术研究培训、课程作业、参加研讨会和会议， 在助学金和手稿准备方面的经验，以及改进教学、指导和实验室的经验 管理技能将支持摩尔博士向独立的过渡。物质与生命的结合 科学方法，体外和体内高度翻译平台的利用，以及两者的整合 细胞外和细胞内对BC基因组稳定性的调节将使摩尔博士能够在 肿瘤学研究。提议的活动将为未来的R01应用程序生成数据，并启动摩尔博士的 致力于推进乳腺癌生物学领域，以改善患者预后为目标的教师生涯。