Tissue mechanics reprograms the tissue to malignancy and metastasis

项目总结 尽管取得了一些突破，提高了许多癌症患者的五年存活率，但从长远来看， 许多患者的预后保持不变。我的团队一直在研究细胞外基质的作用 恶性转化和进展中的细胞外基质和组织张力。我们的发现认为，恶性肿瘤是 由基因修饰引起的张力动态平衡丧失和僵硬的ECM培育的 协同刺激肌动球蛋白改变细胞骨架、细胞信号和基因表达。这项研究 目的是确定张力促进恶性肿瘤的保守分子机制，以确定预测性 用于风险分层的生物标记物，以及开发用于化学预防和抗肿瘤治疗的药物靶点。我们的 飞行员数据显示，僵硬的ECM诱导线粒体应激和代谢重新编程，从而促进 培养和体内的恶性肿瘤和肿瘤侵袭性。研究表明炎症会使ECM变得僵硬 代谢地将髓系细胞重新编程为抑制抗肿瘤免疫的亲肿瘤表型。 我们确定，恶变风险增加的慢性炎症组织中的细胞外基质更坚硬，并表现出 线粒体压力的证据。因此，我们预测组织张力会导致线粒体应激和 妥协抗肿瘤免疫以增强肿瘤细胞的生长、存活和侵袭并诱导基因 促进恶性肿瘤和肿瘤侵袭并促进转移的扰动。我们有2D和3D文化 和小鼠模型，我们可以用它们来测量、操作和修改乳房、胰腺和 胶质母细胞瘤来验证这些预测。我们将通过改进的技术创新来扩展这些方法 分析和监测体内的张力依赖性恶性肿瘤，我们的合作者将协助 工作的技术执行和临床解释。我们已经将分子和药物筛查整合到 确定候选调节剂和抑制化合物，以开发抗肿瘤和化学预防治疗。

PROJECT SUMMARY Despite breakthroughs that have improved the five-year survival of many cancer patients, the long-term prognosis for many patients remains unchanged. My group has been studying the role of the extracellular matrix (ECM) and tissue tension in malignant transformation and progression. Our findings argue that malignancy is fostered by loss of tensional homeostasis induced by genetic modifications and a stiffened ECM that synergistically stimulate actomyosins to alter the cytoskeleton, cell signaling and gene expression. This research aims to identify conserved molecular mechanisms whereby tension promotes malignancy to identify predictive biomarkers for risk stratification and to develop drug targets for chemoprevention and anti-tumor therapies. Our pilot data showed a stiff ECM induces mitochondrial stress and metabolic reprogramming that promote malignancy and tumor aggression in culture and in vivo. Studies revealed inflammation stiffens the ECM to metabolically reprogram the myeloid cells towards a pro-tumor phenotype that represses anti-tumor immunity. We determined that the ECM in chronically inflamed tissues with elevated risk to malignancy is stiffer and exhibits evidence of mitochondrial stress. Thus, we predict that tissue tension induces mitochondrial stress and compromises anti-tumor immunity to enhance tumor cell growth, survival and invasion and induce genetic perturbations that promote malignancy and tumor aggression and foster metastasis. We have 2D and 3D culture and mouse models with which we can measure, manipulate and modify tissue tension in breast, pancreas and glioblastoma to test these predictions. We will expand these approaches with technical innovations that improve analysis and monitoring of tension-dependent malignancy in vivo and our collaborators will assist with the technical execution and clinical interpretation of the work. We have incorporated molecular and drug screens to identify candidate regulators and inhibitory compounds to develop anti-tumor and chemoprevention treatments.