Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

摘要/摘要 乳腺肿瘤通常通过手动触诊来识别，因为它们与正常相比具有明显的“硬度”。 组织.乳腺肿瘤中纤维化病灶的存在与组织增生增加10-50倍有关。 与远处转移和预后差相关。最近的研究表明， 硬度可以在培养的人乳腺类器官中诱导恶性表型，这表明， 细胞外基质的力学性质直接调节肿瘤的转移。然而，如何机械化 力被转化为生化信号以促进肿瘤侵袭和转移在很大程度上是未知的。 我们的初步研究发现，刚性基质刚度激活了一种新的机械转导途径， 诱导上皮-间质转化（EMT）并促进肿瘤转移。因此我们假设 机械力激活林恩激酶，使EMT诱导转录因子TWIST 1 促进肿瘤的侵袭和转移。为了验证这一假设，我们计划1）阐明分子 高组织硬度激活一种新的机械转导级联以促进TWIST 1的机制 核转位和EMT; 2）阐明软基质刚度 阻止TWIST 1核转位并抑制EMT; 3）确定Twist 1 促进体内转移和预测人乳腺癌的机械传导途径 进展

Summary/Abstract 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.