Journal
CANCER LETTERS
Volume 524, Issue -, Pages 245-258Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.10.030
Keywords
NMII isoforms; Matrix stiffness; Cell motility; Phospho-regulation; Mechanotransduction
Categories
Funding
- National Natural Science Foundation of China [U19A2006, 12132004, 11772088, 11802056, 31800780, 11972111, 31900940, 32071304, 32171309, 32171395]
- Sichuan Science and Technology Program [21YJ0130]
- China Postdoctoral Science Foundation [2019T120831]
- Joint Funds of Center for Engineering Medicine [ZYG-X2021YGLH017, ZYGX2021YGLH010, YGX2021YGLH023]
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The study found that NMIIA plays a role in establishing cell polarity, while NMIIB is involved in generating traction force and polarized distribution, depending on substrate stiffness. Substrate stiffness modulates the distribution and activation of NMII isoforms through multiple signaling pathways and kinase-specific phosphoregulation.
The stiffening of the extracellular matrix (ECM) during tumor progression results in an increase in cancer cell motility. In cell migration, two major isoforms of non-muscle myosin II (NMII), NMIIA and NMIIB, are expressed and assembled into the cytoskeleton. However, the isoform-specific regulatory roles of NMIIA and NMIIB as well as the underlying mechanisms in response to mechanical cues of the ECM are still elusive. Here, based on polyacrylamide (PAA) gels with tunable elastic modulus, we mimicked the mechanical properties of tumor tissue at different stages of breast cancer in vitro and investigated the distinct roles of NMII isoforms in the regulation of substrate stiffness. We demonstrate that NMIIA is engaged in establishing cell polarity by facilitating lamellipodia formation, focal adhesion turnover, and actin polymerization at the cell leading edge, while NMIIB is recruited to the cell perinuclear region and contributes to traction force generation and polarized distribution, both in a substrate stiffness-dependent manner. We further validated that substrate stiffness modulates the distribution and activation of NMII isoforms via the Rac1/p-PAK1/pS1916-NMIIA and PKC zeta/pS1935-NMIIB signaling pathways in a site- and kinase-specific phosphoregulation manner. Our study is helpful for understanding the mechanotransduction of cancer cells and provides inspiration for molecular targets in antimetastatic therapy.
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