Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

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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.