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（Elizabeth Moore）博士寻求拟议的指导研究科学家发展奖 （K01）获得必要的培训和经验，以成为独立翻译的临床 - 专注于肿瘤微环境调节乳腺癌（BC）基因组稳定性和 治疗性抗性。卑诗省治疗性抗性仍然是成功治疗的主要障碍， 特别是在侵略性三重阴性（TNBC）亚型中。但是，目前尚不清楚治疗如何 反应受肿瘤微环境的物理和生物学特征的影响，以及 角色改变了DNA损伤响应（DDR）机制和代谢重编程的作用。在 特别是，尚待阐明细胞外基质（ECM）的纤维化重塑如何 杂种微环境，影响BC风险和耐药性的标志性特征。鉴于这些 连接，拟议研究的总体目标是确定基质介导的机制 BC治疗抗性。 AIM 1将确定纤维化ECM对BC DNA损伤响应的影响 （DDR）。 AIM 2将测试纤维化ECM如何调节肿瘤细胞的DDR和代谢 互动。 AIM 3将测试体内纤维化ECM，DDR和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，其中纤维化ECM的特征 可以选择性地调整重塑。 AIM 3将利用乳腺纤维化的人源化小鼠模型 和TNBC使用人类BC细胞系和TNBC的患者衍生Xenographtics。一种多学科的方法， 包括经典分子技术，基因表达分析，代谢组学和海马代谢 分析和高级成像将用于实现这些目标和候选人获取 其他技术技能。 Moore博士的心理是体外工程领域的领先专家和体内模型的专家 研究肿瘤微环境相互作用。联合官员将在基因组稳定领域提供专业知识 以及DDR，细胞代谢和代谢组学以及乳腺癌的临床方面。教师专业知识 在康奈尔大学，进一步的肿瘤学研究中的跨学科合作非常强大 通过培训环境和出色的核心设施加强。计划的职业发展 活动，包括技术研究培训，课程，下水道和会议的出勤， 具有赠款和手稿准备的经验，教学，指导和实验室的完善 管理技能将支持摩尔博士向独立的过渡。身体和生命的融合 科学方法，利用高度转化的体外和体内平台以及两者的整合 BC基因组稳定性的细胞外和细胞内调节将使摩尔博士能够在 肿瘤学研究。拟议的活动将为未来的R01应用程序生成数据，并启动Moore博士的数据 教师在推进乳腺癌生物学领域的职业，目的是改善患者提示。