Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

基质硬度对肿瘤侵袭和转移的调节

• 批准号: 10557145
• 负责人: Jing Yang
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10557145
• 关键词: 3-Dimensional; Automobile Driving; Biochemical; Breast Cancer Patient; Cell Nucleus; Collagen Fiber; Cytoplasm; Data; Distant Metastasis; EPHA2 gene; Ensure; Epithelium; Extracellular Matrix; Family; G3BP1 gene; Genetic Transcription; Goals; Hardness; Human; Invaded; 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; Protein Dephosphorylation; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Site; TWIST1 gene; TYK2; Testing; Tissues; Translating; Tumor Cell Invasion; Tumor Promotion; Work; arm; 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

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” 组织。乳腺肿瘤中纤维化病灶的存在与组织增加 10-50 倍相关 僵硬并与远处转移和不良结果相关。最近的研究表明，增加矩阵 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 细胞外基质的力学特性直接调节肿瘤的转移。然而，如何机械化 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机械传导途径 诱导上皮间质转化（EMT）并促进肿瘤转移。因此我们假设 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。为了检验这个假设，我们计划 1) 阐明分子 高组织硬度激活新型机械传导级联以促进 TWIST1 的机制 核易位和EMT； 2）阐明软基体刚度的新分子机制 防止 TWIST1 核易位并抑制 EMT； 3) 确定 Twist1 的参与情况 促进体内转移和预测人类乳腺癌的机械传导途径 进展。