Regulation of Cancer Cell Metastasis by Mechanical Force

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The objective of the project is to unravel the role of mechanical forces and microenvironment in cancer metastasis by (a) measuring the cellular force history, and (b) searching for the molecular mechanism of force transduction to metastasis. The PIs have recently discovered that human colon carcinoma (HCT-8) cells exhibit a dissociative, metastasis-like phenotype (MLP) in vitro when cultured on substrates with appropriate mechanical softness. This novel finding suggests that the onset of metastasis may be fundamentally linked to the mechanical microenvironment of the tumor.Intellectual merit: It is hypothesized that the stiffness dependent metastasis is mediated by the temporal force histories of the cells (over days) that they generate in response to their mechanical micro-environment. Cells transduce the prolonged force signal to biochemical pathways that determine their transition to highly metastatic state. The hypothesis will be tested by:(1) Measuring temporal evolution of cell force (cell-cell, cell-substrate) for HCT-8 cells over days to weeks at a single cell or subcellular scale by developing a novel cell force sensor. (2) Searching for molecular mechanisms for MLP by simultaneously interrogating cytoskeletal and molecular signatures of the cells as they go through metastatic-like transition. Broader impact: Despite the significant improvement in both the early diagnosis and treatment of cancer patients, metastasis is still the major cause of mortality. Understanding how the mechanical microenvironment regulates cancer cell biological processes responsible for metastasis represents a newly developing paradigm that has the potential to add novel anti-metastasis therapeutics to the current arsenal. The research will be integrated with education and outreach by (1) developing a new graduate level interdisciplinary course, (2) developing a hands-on instructional module for local children?s museum, (3) recruiting REU students from diverse backgrounds, (4) fostering a graduate student leadership group, (5) developing a web page to disseminate the new knowledge and tools to be developed.