Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

基质硬度对肿瘤侵袭和转移的调节

基本信息

批准号：
10374409
负责人：
Jing Yang
金额：
$ 36.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374409
关键词：
3-Dimensional Automobile Driving Biochemical Breast Cancer Patient Cell Nucleus Collagen Fiber Cytoplasm Data Distant Metastasis EPHA2 gene Ensure Epithelial Extracellular Matrix Family Genetic Transcription Goals Hardness Human LYN gene Link Mammary Neoplasms Mammary gland Manuals Mesenchymal Molecular Mus Neoplasm Metastasis Nodule Normal tissue morphology Nuclear Nuclear Translocation Organoids Outcome Palpation Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Play Proteins Regulation Research Role Signal Pathway Signal Transduction Site TWIST1 gene TYK2 Testing Tissues Transitional Cell Translating Tumor Cell Invasion Work arm base breast cancer progression cancer cell clinically significant in vivo malignant breast neoplasm malignant phenotype mammary mammary epithelium mechanical force mechanical properties mechanotransduction novel prevent reconstitution recruit response therapeutic target transcription factor tumor tumor microenvironment

项目摘要

Breast tumors are often identified by manual palpation due to their apparent “hardness” compared to normal tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix stiffness can induce a malignant phenotype in cultured human mammary organoids, suggesting that mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown. Our preliminary studies found that rigid matrix stiffness activates a novel mechanotransduction pathway to induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We therefore hypothesize that mechanical forces activates the LYN kinase to allow the EMT-inducing transcription factor TWIST1 to promote tumor invasion and metastasis. To test this hypothesis, we plan to 1) To elucidate the molecular mechanism by which high tissue stiffness activates a novel mechanotransduction cascade to promote TWIST1 nuclear translocation and EMT; 2) To elucidate the novel molecular mechanism by which soft matrix stiffness prevents TWIST1 nuclear translocation and inhibit EMT; 3) To determine the involvement of the Twist1 mechanotransduction pathway in promoting metastasis in vivo and in predicting human breast cancer progression.

乳腺肿瘤通常通过手动触诊来识别，因为与正常乳腺肿瘤相比，它们具有明显的“硬度” 乳腺肿瘤中纤维化灶的存在与组织增加 10-50 倍相关。最近的研究表明，基质的增加与远处转移和不良预后相关。僵硬可以在培养的人类乳腺类器官中诱导恶性表型，这表明然而细胞外基质的力学特性直接调节肿瘤的转移。力量如何转化为生化信号以促进肿瘤侵袭和转移尚不清楚。我们的初步研究发现，刚性基质刚度激活了一种新的力传导途径诱导上皮间质转化（EMT）并促进肿瘤转移。机械力激活 LYN 激酶，使 EMT 诱导转录因子 TWIST1 促进肿瘤侵袭和转移为了检验这一假设，我们计划 1) 阐明分子机制。高组织硬度激活新型机械传导级联以促进 TWIST1 的机制核转位和EMT；2）阐明软基质刚度的新分子机制防止TWIST1核易位并抑制EMT；3)确定Twist1的参与；促进体内转移和预测人类乳腺癌的机械传导途径进展。