ECM Stiffness as a Regulator of Tumor Cell Dissemination and Dormancy

ECM 硬度作为肿瘤细胞传播和休眠的调节剂

• 批准号: 9130485
• 负责人: Patricia J Keely
• 金额: $ 28.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130485
• 关键词: Address; Affect; Animals; Archives; Behavior; Biological Markers; Biopsy Specimen; Breast Cancer Patient; Cell Respiration; Cells; Clinical; Collagen; Cytoplasm; DDR1 gene; Data; Deposition; Devices; Disease Progression; Environment; Extracellular Matrix; Fibroblasts; Fibrosis; Fluorescence; Glycolysis; Head and Neck Squamous Cell Carcinoma; Human; Hypoglycemia; Hypoxia; Image; Infiltration; Label; Laser Scanning Microscopy; Lead; Life; Lung; Mammary Neoplasms; Maps; Mechanical Stress; Metabolic; Metabolism; Mitochondria; Molecular; Mus; NADH; Neoplasm Metastasis; Outcome; PTK2 gene; Pathway interactions; Patients; Population; Primary Neoplasm; Process; Proliferation Marker; Property; Research; Resolution; Sampling; Signal Transduction; Site; Staging; Stress; Stromal Cells; cofactor; density; in vivo; intravital imaging; macrophage; metaplastic cell transformation; migration; mouse model; neoplastic cell; tumor; tumor microenvironment; tumor progression

We hypothesize that dense collagen matrices create a mechanical "stress" environment that alters cellular invasion and cellular metabolism, and promotes, depending on the ECM composition, proliferation or dormancy at metastatic target sites. We propose that changes in the fluorescence lifetime of NAD(P)H and FAD can be used 1) in the research setting to track and understand disease progression, macrophage infiltration, disseminated tumor cells (DTCs) and dormancy; and 2) developed for use in the clinical setting to provide early information about tumor progression and dissemination. NAD(P)H and FAD are particularly attractive potential biomarkers for clinical use, as they are endogenous signals that require no external label and can be imaged in fresh or fixed biopsy samples. These questions will be addressed in three specific aims: 1) Determine whether local regions of increased stress (mechanical, hypoxic or hypoglycemic) alter the metabolic signature of tumor and stromal cells; 2) Investigate mechanisms by which fibrosis affects the dormancy and metabolic signatures of DTCs ;3) Determine whether metabolic and dormancy signatures are useful predictors of stage and outcome in human HNSCC and breast cancer patients.

我们假设致密的胶原蛋白基质会产生机械“压力”环境，从而改变 细胞侵袭和细胞代谢，并根据 ECM 成分促进， 转移靶位点的增殖或休眠。我们建议荧光的变化 NAD(P)H 和 FAD 的生命周期可用于 1) 在研究环境中跟踪和了解疾病 进展、巨噬细胞浸润、播散性肿瘤细胞 (DTC) 和休眠； 2) 开发用于 在临床环境中使用以提供有关肿瘤进展和传播的早期信息。 NAD(P)H 和 FAD 是临床应用中特别有吸引力的潜在生物标志物，因为它们是内源性信号， 不需要外部标签，并且可以在新鲜或固定的活检样本中成像。这些问题将会 解决三个具体目标： 1) 确定局部区域是否存在压力增加（机械、 缺氧或低血糖）改变肿瘤和基质细胞的代谢特征； 2）调查 纤维化影响 DTC 休眠和代谢特征的机制；3) 确定 代谢和休眠特征是否是人类阶段和结果的有用预测因子 HNSCC 和乳腺癌患者。