Cancer Cell Mechanotransduction

 

Yong Zhou

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Plasma membrane (PM) curvature defines cell shape and is a fundamental mechanical property of mammalian cells. Since the 1970’s, micropatterning of cultured cells, and high-content imaging of intact tissues, have established that essential cell functions depend on cell shape. Specifically, DNA synthesis, growth and proliferation are more stimulated, whereas terminal differentiation and apoptosis are lower, in more rounded and flatter cells than the same cells in elongated shapes. Growth and proliferation of pancreatic, gastrointestinal, breast and prostate tumor cells also depend on cell shape. A lipid-anchored small GTPase K-Ras4B localizes to the PM, regulates cell growth/proliferation and is a driver of ~1/3 of all human cancer. In mouse tumor allografts, melanoma cells expressing a K-Ras4B oncogenic mutant display a rounded shape, while inhibiting K-Ras4B signaling causes the melanoma cells to adopt an elongated shape. A recent siRNA screening of a cohort of 92 human pancreatic, lung, intestinal cancer lines also identifies K-Ras4B mutants as determining factors for the epithelial, as opposed to elongated, shape of cancer cells. Thus, K-Ras4B may play important roles in the PM curvature-dependent growth/proliferation of cancer cells.

 

We combine nano-engineering, biophysics and quantitative super-resolution imaging to evaluate the potential membrane curvature sensing of the lipid-anchored small GTPases, with a focus on K-Ras, in synthetic vesicles and mammalian cells (non-transformed and tumor cells).   Our findings provide a molecular mechanism for the long-observed correlation between cell morphological changes and cell functions, thus a new perspective on cancer cell mechanosensing.