Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

University Of California, San Diego, La Jolla CA

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Abstract

Summary/Abstract The survival of individuals with Down syndrome (DS) due to trisomy 21 has increased drastically in recent decades, resulting in large numbers of adults with DS. Studies indicate that individuals with Down syndrome have over 10-fold lower risk of developing breast cancer compared to the general population. The reduction of breast cancer is significantly higher than the reduction of general solid tumors (about 2-fold) in individuals with DS. It has long been hypothesized that chromosome 21 might contain cancer suppressor genes. However, it remains largely unknown what these tumor suppressor genes are and specifically no unique breast cancer suppressor genes have been uncovered. Breast tumors are often identified by manual palpation due to their apparent “hardness” compared to normal tissue. A 10-50-fold increase in tissue stiffness in certain breast tumors correlates with distant metastasis and poor outcome. Our ongoing studies found that rigid matrix stiffness activates a novel mechanotransduction pathway to induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We show that high extracellular matrix stiffness activates nuclear localization of an EMT-inducing transcription factor TWIST1 to promote tumor invasion and metastasis. Interestingly, our preliminary data suggest that deregulation of this mechanism due to trisomy 21 could contribute to suppression of breast cancer development and progression. To test this hypothesis, we plan to 1) determine whether and how inhibiting EMT by gene alternation due to trisomy 21 contributes to breast tumor suppression in human and mouse mammary organoids; 2) determine whether and how inhibiting EMT by gene alternation due to trisomy 21 contributes to breast tumor suppression in breast tumor xenografts in mice.