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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要最近，我们在乳腺癌中发现了白脂肪组织（WAT）的意外且有趣的作用。我们的过去的研究表明，WAT细胞外基质（ECM）的机械性能调节肿瘤细胞入侵，这是转移的关键限制步骤，这些特性在肥胖症中发生了改变，有助于肥胖患者乳腺癌的患病率增加和预后较差。现在，最近的初步数据从我们的实验室进来，还表明脂肪细胞机械性能可能同样重要。然而，脂肪细胞力学如何随肥胖而变化以及这些变化对ECM重塑和肿瘤侵袭仍然在很大程度上不清楚。理解这些联系很重要，原因有几个：首先，虽然WAT的生化功能广为人知会导致乳腺癌的发病机理，但 WAT机械性能对乳腺癌侵袭的影响在很大程度上没有探索。第二，我们的初步数据表明，肥胖个体中WAT的异常重塑促进了由于脂肪细胞脂质损失，转分解为肌纤维细胞以及ECM沉积的结果变化所有影响水力学的。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机械性能和肿瘤细胞代谢来协同促进侵袭。阐明这些参数如何相互联系对于减轻乳腺癌负担至关重要，并且需要发现脂肪细胞和肿瘤细胞的单细胞性质如何影响WAT的计算方法力学和肿瘤细胞侵袭。通过三个集中和互补的特定目标，提议迭代伴侣的肿瘤细胞侵入WAT的计算模型，材料表征脂肪细胞和ECM，工程细胞培养模型以及转基因小鼠模型，可视化和在乳腺中操纵WAT。此外，单细胞和空间RNA转录组学，耦合使用先进的生物信息学方法和人类标本，将确定相关的分子机制和对患者预后的潜在价值。特别是，我们将（1）定义WAT物理特性乳房作为肥胖的作用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物理特性和肿瘤细胞代谢的影响，（3）建立肿瘤诱导脂质损失的分子基础，瘦肉与肥胖脂肪细胞，并确定其对WAT的影响物理特性和肿瘤侵袭。这些研究将确定特定的肥胖依赖性变化机械性能及其相关的分子机制，这些机制将有助于预测乳腺癌的风险基于组织学分析的给定患者的入侵。