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

基本信息

批准号：
10053272
负责人：
VALERIE MARIE WEAVER
金额：
$ 96.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10053272
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 Psychological reinforcement Refractory Research Resistance Risk Risk stratification Role Signal Transduction Stress Testing Tissues Tumor Immunity Work cancer survival cell growth improved in vivo innovation insight mortality mouse model neoplastic cell outcome forecast patient stratification predictive marker programs three dimensional cell culture tumor tumor progression

项目摘要

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.

项目概要尽管取得的突破提高了许多癌症患者的五年生存率，但长期来看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）和恶性转化和进展中的组织张力。我们的研究结果表明，恶性肿瘤是基因修饰引起的张力稳态丧失和 ECM 硬化导致协同刺激肌动球蛋白以改变细胞骨架、细胞信号传导和基因表达。这项研究旨在确定紧张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志物以及开发化学预防和抗肿瘤治疗的药物靶点。我们的试点数据显示，僵硬的 ECM 会诱导线粒体应激和代谢重编程，从而促进培养物和体内的恶性肿瘤和肿瘤侵袭。研究表明炎症会使 ECM 变硬通过代谢将骨髓细胞重新编程为抑制抗肿瘤免疫的促肿瘤表型。我们确定，恶性肿瘤风险较高的慢性炎症组织中的 ECM 更坚硬，并且表现出线粒体应激的证据。因此，我们预测组织张力会诱导线粒体应激并损害抗肿瘤免疫，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侵袭并促进转移的扰动。我们有2D和3D文化以及小鼠模型，我们可以用它们来测量、操纵和修改乳房、胰腺和胶质母细胞瘤来检验这些预测。我们将通过技术创新来扩展这些方法，以提高体内张力依赖性恶性肿瘤的分析和监测，我们的合作者将协助工作的技术执行和临床解释。我们将分子和药物筛选结合起来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。