Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

描述（由申请人提供）：由于乳房肿瘤与正常组织相比明显的“硬度”，通常通过手触诊来识别。乳腺肿瘤中纤维化灶的存在与组织硬度增加10-50倍相关，并与远处转移和不良预后相关。最近的研究表明，在培养的人乳腺腺泡中，增加基质刚度可诱导恶性表型，提示细胞外基质的力学特性直接调节肿瘤转移。然而，机械力如何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个关键的发育程序，称为上皮-间充质转化（EMT），以促进肿瘤转移。因此，我们假设机械力通过一种新的机械转导途径调节emt诱导的转录因子，从而促进肿瘤的侵袭和转移。为了验证这一假设，我们计划1-2)剖析机械力激活emt诱导转录因子的分子机制；3)确定emt诱导转录因子的机制调控在体内促进乳腺癌转移和预测乳腺癌患者长期生存中的作用。

DESCRIPTION (provided by applicant): 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 acini, 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 key developmental program termed Epithelial- Mesenchymal Transition (EMT) to promote tumor metastasis. We therefore hypothesize that mechanical forces regulate EMT-inducing transcription factors through a novel mechanotransduction pathway to promote tumor invasion and metastasis. To test this hypothesis, we plan to 1-2) dissect the molecular mechanism by which mechanical forces activate EMT-inducing transcription factors; 3) determine the involvement of mechanoregulation of EMT-inducing transcription factors in promoting metastasis in vivo and in predicting long-term survival in human breast cancer patients.