Tissue mechanics reprograms the tissue to malignancy and metastasis

组织力学将组织重新编程为恶性肿瘤和转移

• 批准号: 10478193
• 负责人: VALERIE MARIE WEAVER
• 金额: $ 94.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478193
• 关键词: Actomyosin; Aggressive behavior; Biological Markers; Breast; Cancer Patient; Chemoprevention; Chronic; Clinical; Cytoskeleton; Data; Disease; Drug Screening; Drug Targeting; Evolution; Exhibits; Extracellular Matrix; Fostering; Gene Expression; Genetic; Glioblastoma; Homeostasis; Inflammation; Malignant - descriptor; Malignant Neoplasms; Measures; Mechanics; Metabolic; Metastatic to; Mitochondria; Modification; Molecular; Monitor; Myeloid Cells; Neoplasm Metastasis; Pancreas; Patients; Phenotype; Prognosis; Psychological reinforcement; Refractory; Research; Resistance; Risk; Role; Signal Transduction; Stress; Testing; Tissues; Tumor Immunity; Work; cancer survival; cell growth; improved; in vivo; innovation; insight; mortality; mouse model; neoplastic cell; patient stratification; predictive marker; programs; risk stratification; three dimensional cell culture; tumor; tumor progression

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.

项目摘要 尽管突破改善了许多癌症患者的五年生存率，但长期 许多患者的预后保持不变。我的小组一直在研究细胞外基质的作用 （ECM）和组织张力在恶性转化和进展中。我们的发现认为恶性肿瘤是 由遗传修饰引起的紧张稳态和僵硬的ECM引起的损失而产生的 协同刺激肌动蛋白改变细胞骨架，细胞信号传导和基因表达。这项研究 旨在确定张力促进恶性肿瘤以识别预测性的保守分子机制 用于风险分层的生物标志物，并开发用于化学预防和抗肿瘤疗法的药物靶标。我们的 试验数据显示，僵硬的ECM诱导线粒体应力和代谢重编程，以促进 培养和体内的恶性和肿瘤侵略。研究表明，炎症使ECM僵硬 代谢重新编程髓样细胞朝着抑制抗肿瘤免疫力的促肿瘤表型。 我们确定慢性发炎的组织中的ECM具有升高恶性肿瘤的性能是更硬的，并且展示 线粒体应力的证据。因此，我们预测组织张力会诱导线粒体应力和 损害抗肿瘤免疫以增强肿瘤细胞的生长，存活和侵袭并诱导遗传 促进恶性肿瘤和肿瘤攻击和促进转移的扰动。我们有2D和3D文化 和小鼠模型，我们可以通过这些模型进行测量，操纵和修改乳房，胰腺和 胶质母细胞瘤测试这些预测。我们将通过改进的技术创新扩展这些方法 分析和监测体内张力依赖性恶性肿瘤和我们的合作者将有助于协助 技术执行和临床解释。我们已经将分子和药物筛选纳入 确定候选调节剂和抑制性化合物，以开发抗肿瘤和化学预防治疗。