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