Cells sample and respond to extracellular matrix (ECM) stiffness with actomyosin-generated contractile forces in a process known as rigidity mechanosensing.  In cancer, the rigidity of the tumor-associated ECM has been implicated in promoting invasive migration by cancer cells via mechanical signaling pathways.  We have previously shown that cancer cell contractile forces are dependent on ECM rigidity and are predictive of ECM degradation by invadopodia, actin-rich subcellular protrusions which are thought to be essential for invasion and metastasis.  Cellular contractility is regulated by myosin light chain kinase (MLCK) and rho-associated kinase (ROCK).  Numerous studies have utilized common kinase inhibitors to show that MLCK and ROCK influence invasive migration similarly.  However, recent work has shown that the isoforms ROCK1 and ROCK2 participate in some non-redundant signaling pathways that depend on cellular spatial localization.  In addition, MLCK also displays preferential cellular localization which results in little effect on sustained force generation.  In support of these differences, we present data utilizing siRNA against the two ROCK isoforms and MLCK that reveal diverse effects on actomyosin contractility and invadopodia activity.  These results suggest that only a ROCKI-dependent mechanical signaling pathway may be involved in directly regulating both contractile forces and ECM degradation.

Role for ROCK1-dependent contractility in proteolytic degradation by cancer cell invadopodia

247th National Meeting (2014)

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