Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

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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.