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

项目摘要 候选人伊丽莎白摩尔博士寻求拟议的指导研究科学家发展奖 (K01) 获得成为独立转化临床医生所需的培训和经验- 科学家专注于乳腺癌（BC）基因组稳定性的肿瘤微环境调节和 治疗抵抗。 BC 治疗耐药性仍然是成功治疗的主要障碍， 特别是在攻击性三阴性（TNBC）亚型中。但目前尚不清楚如何治疗 反应受到肿瘤微环境的物理和生物学特征的影响， 改变DNA损伤反应（DDR）机制和代谢重编程在这一过程中发挥着作用。在 特别是，细胞外基质（ECM）的纤维化重塑是如何进行的仍有待阐明，细胞外基质是 促肿瘤微环境的标志性特征，影响 BC 风险和耐药性。鉴于这些 连接，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。目标 1 将确定纤维化 ECM 对 BC DNA 损伤反应的影响 （DDR）。目标2将测试纤维化ECM如何调节肿瘤细胞的DDR和代谢及其相互关系 互动。目标 3 将测试纤维化 ECM、DDR 和体内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度 3D 组织培养系统，其中纤维化 ECM 的特征 改造可以选择性地调整。目标 3 将利用乳腺纤维化的人源化小鼠模型 TNBC 使用人类 BC 细胞系和患者来源的 TNBC 异种移植物。多学科方法， 包括经典分子技术、基因表达分析、代谢组学和海马代谢 分析和先进的成像将用于实现这些目标，并让候选人获得 额外的技术技能。摩尔博士的导师是体外和体内模型工程领域的领先专家 研究肿瘤与微环境的相互作用。共同导师将提供基因组稳定性领域的专业知识 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 康奈尔大学和其他大学在肿瘤学研究方面的跨学科合作异常强大 培训环境和卓越的核心设施强化了这一点。规划的职业发展 活动，包括技术研究培训、课程作业、参加研讨会和会议， 资助和手稿准备以及教学、指导和实验室完善的经验 管理技能将支持摩尔博士向独立过渡。身体与生活的结合 科学方法、高度转化的体外和体内平台的利用以及两者的整合 BC 基因组稳定性的细胞外和细胞内调节将使 Moore 博士能够在 肿瘤学研究。拟议的活动将为未来的 R01 应用生成数据并推出 Dr. Moore 的 教师致力于推进乳腺癌生物学领域，以改善患者预后。

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.