Mechanical properties of adipose tissue and its effect on breast cancer

项目总结 我们最近发现白色脂肪组织(WAT)在乳腺癌中的一个意想不到的和有趣的作用。我们的 以往的研究证实，Wat细胞外基质(ECM)的力学性质调节肿瘤细胞 侵袭性是转移的关键限速步骤，这些特性在肥胖中发生改变，从而导致 肥胖患者乳腺癌患病率增加，预后较差。现在，最近的初步数据 来自我们实验室的研究还表明，脂肪细胞的机械性能可能也同样重要。然而， 肥胖时脂肪细胞力学如何变化，这些变化对细胞外基质重塑和 肿瘤的侵袭在很大程度上仍不清楚。理解这些联系很重要，原因有几个：第一， 虽然众所周知Wat的生化功能与乳腺癌的发病机制有关，但Wat的 水力学特性对乳腺癌侵袭的影响在很大程度上还没有被探索。第二，我们的初选 数据表明，肥胖者Wat的异常重塑促进了乳腺癌的侵袭，这是由于 脂肪细胞的脂肪丢失，转分化为肌成纤维细胞，以及相应的细胞外基质沉积的变化 这会影响WAT的机械结构。最后，我们的初步结果还表明，肿瘤引起的血脂损失可能 通过改变Wat的机械性能和肿瘤细胞代谢协同促进侵袭。澄清 这些参数如何相互联系将是减少乳腺癌负担的关键，并需要 揭示脂肪细胞和肿瘤细胞的单细胞特性如何影响水的计算方法 力学和肿瘤细胞侵袭。通过三个集中和相辅相成的具体目标，拟议的 工作迭代地将肿瘤细胞侵袭的计算模型耦合到WAT中，材料表征 脂肪细胞和细胞外基质，工程细胞培养模型和转基因小鼠模型，允许可视化和 乳腺中的WAT的操作。此外，单细胞和空间RNA转录切割，耦合 利用先进的生物信息学方法和人体样本，将确定相关的分子 其机制及对患者预后的潜在价值。具体来说，我们将(1)在中定义WAT物理属性 乳腺作为肥胖的函数，决定了它们对肿瘤侵袭的影响，(2)确定了二者的协同作用 肿瘤诱导的脂质损失对水的物理性质和肿瘤细胞代谢的影响，以及(3)建立 肿瘤诱导肥胖与瘦脂肪细胞脂质丢失的分子基础及其对水分的影响 物理特性与肿瘤侵袭的关系。这些研究将确定特定的肥胖依赖的水变化 有助于预测乳腺癌风险的机械特性及其相关的分子机制 根据组织学分析，特定患者的侵袭性。

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.