Mechanical properties of adipose tissue and its effect on breast cancer

脂肪组织的力学特性及其对乳腺癌的影响

• 批准号: 10737165
• 负责人: Claudia Fischbach
• 金额: $ 53.1万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737165
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Biochemical; Bioinformatics; Biology; Breast; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast cancer metastasis; Calibration; Cancer Burden; Cancer Prognosis; Cause of Death; Cell Culture Techniques; Cells; Coculture Techniques; Computer Models; Computer Simulation; Computing Methodologies; Coupled; Couples; Coupling; Data; Data Set; Deposition; Disparity; Elements; Engineering; Extracellular Matrix; Frequencies; Gene Expression; Gene Expression Profile; Genetic; Histologic; Histology; Human; Inflammatory; Invaded; Ligands; Link; Lipids; Malignant Neoplasms; Mammary gland; Mechanics; Methods; Modeling; Molecular; Myofibroblast; Neoplasm Metastasis; Obesity; Obesity Epidemic; Pathogenesis; Pathologic; Patients; Phenotype; Play; Prevalence; Process; Prognosis; Property; RNA; Role; Sampling; Shapes; Specimen; Technology; Testing; Thinness; Time; Tissues; Transgenic Mice; Tumor Cell Invasion; Tumor Promotion; Visualization; Work; adipokines; advanced breast cancer; biological systems; biophysical properties; cell motility; clinically relevant; computer studies; effective therapy; experimental study; genetic signature; improved; in vivo; insight; interstitial; malignant breast neoplasm; mechanical properties; mouse model; neoplastic cell; novel; obese patients; obese person; particle; patient prognosis; physical property; receptor; risk prediction; simulation; transcriptome sequencing; transcriptomics; transdifferentiation; tumor; tumor metabolism

PROJECT SUMMARY We recently discovered an unexpected and intriguing role for white adipose tissue (WAT) in breast cancer. Our past studies identified that the mechanical properties of WAT extracellular matrix (ECM) regulate tumor cell invasion, a key rate-limiting step of metastasis, and that these properties are altered in obesity, contributing to the increased prevalence and worse prognosis of breast cancer in obese patients. Now, recent preliminary data from our labs additionally suggest that adipocyte mechanical properties may be similarly important. However, how adipocyte mechanics change with obesity and which effect these changes have on ECM remodeling and tumor invasion remains largely unclear. Understanding these connections is important for several reasons: First, while the biochemical functions of WAT are widely known to contribute to the pathogenesis of breast cancer, the influence of WAT mechanical properties on breast cancer invasion is largely unexplored. Second, our preliminary data suggest that aberrant remodeling of WAT in obese individuals promotes breast cancer invasion due to adipocyte lipid loss, transdifferentiation into myofibroblasts, and consequential changes in ECM deposition all of which affect WAT mechanics. Last, our preliminary results also indicate that tumor-induced lipid loss may synergistically promote invasion by changing WAT mechanical properties and tumor cell metabolism. Elucidating how these parameters are interconnected will be critical to decrease breast cancer burden and requires computational methods to uncover how single-cell properties of adipocytes and tumor cells affect WAT mechanics and tumor cell invasion. Through three focused and complementary Specific Aims, the proposed work iteratively couples computational models of tumor cell invasion into WAT, materials characterization of adipocytes and ECM, engineered cell culture models, and transgenic mouse models that allow visualization and manipulation of WAT in the mammary gland. Furthermore, single cell and spatial RNA transcriptomics, coupled with advanced bioinformatics approaches and human specimens, will determine the associated molecular mechanisms and potential value to patient prognosis. In particular, we will (1) define WAT physical properties in the breast as a function of obesity and determine their effect on tumor invasion, (2) determine the synergistic effect of tumor-induced lipid loss on WAT physical properties and tumor cell metabolism, and (3) establish the molecular basis of tumor-induced lipid loss in lean versus obese adipocytes and determine their effect on WAT physical properties and tumor invasion. These studies will identify specific obesity-dependent changes in WAT mechanical properties and their associated molecular mechanisms that will help predict the risk of breast cancer invasion for a given patient based on histological analysis.

项目摘要 我们最近发现了一个意想不到的和有趣的作用，白色脂肪组织（WAT）在乳腺癌。我们 过去的研究表明，WAT细胞外基质（ECM）的力学性质调节肿瘤细胞的生长， 侵袭，转移的关键限速步骤，并且这些特性在肥胖症中改变，有助于 肥胖患者中乳腺癌的患病率增加和预后更差。最近的初步数据显示 另外表明脂肪细胞的机械特性可能同样重要。然而，在这方面， 脂肪细胞力学如何随肥胖而变化，以及这些变化对ECM重塑和 肿瘤的侵袭性在很大程度上仍不清楚。理解这些联系很重要，原因有几个：首先， 虽然WAT的生化功能被广泛认为有助于乳腺癌的发病机制， WAT机械性能对乳腺癌侵袭的影响在很大程度上还未被探索。第二，我们的初步 数据表明，肥胖个体中WAT的异常重塑促进了乳腺癌的侵袭， 脂肪细胞脂质损失，转分化为肌成纤维细胞，以及ECM沉积的相应变化， 这会影响WAT机制。最后，我们的初步结果还表明，肿瘤诱导的脂质损失可能 通过改变WAT机械特性和肿瘤细胞代谢协同促进侵袭。阐明 这些参数如何相互关联对于降低乳腺癌负担至关重要， 计算方法来揭示脂肪细胞和肿瘤细胞的单细胞特性如何影响WAT 力学和肿瘤细胞侵袭。通过三个重点突出、相辅相成的具体目标， 工作迭代地将肿瘤细胞侵袭的计算模型耦合到WAT中， 脂肪细胞和ECM、工程化细胞培养模型和转基因小鼠模型， 在乳腺中操纵WAT。此外，单细胞和空间RNA转录组学，耦合 与先进的生物信息学方法和人类标本，将确定相关的分子 对患者预后的潜在价值。特别是，我们将（1）定义WAT物理属性， 乳腺癌作为肥胖的函数，并确定其对肿瘤侵袭的影响，（2）确定协同作用， 肿瘤诱导的脂质损失对WAT物理性质和肿瘤细胞代谢的影响，以及（3）建立 肿瘤诱导的瘦型与肥胖型脂肪细胞脂质损失的分子基础，并确定其对WAT的影响 物理性质和肿瘤侵袭。这些研究将确定WAT中特定的肥胖依赖性变化 机械性能及其相关的分子机制，这将有助于预测乳腺癌的风险 基于组织学分析确定给定患者的侵袭。