Mechanotransduction Pathways in Rigidity-sensitive and Rigidity-insensitive Cancer Cells

Tissues and cells are subject to many physical forces, such as stress and strain. It has long been known that cells sense and respond to these physical forces. On a cellular level, the rigidity of surrounding extracellular matrix profoundly influences the physical forces sensed by normal cells and can inhibit or drive proliferation. Cancer cells, however, show varying growth responses to changes in rigidity. Comparison of multiple cell lines revealed that cancer cell growth responses generally fall into one of two categories: rigidity-sensitive or rigidity-insensitive. Cancer cells that are rigidity-insensitive grow efficiently regardless of their substrate rigidity, and likewise colonize soft tissue well. Rigidity-sensitive cancer cells proliferate more slowly on rigidities of soft tissue, but increase their growth dramatically as rigidity increases. These cells do not colonize soft tissue as well as rigidity-insensitive cells. To understand the mechanism by which cancer cells differ in their rigidity sensitivities, previously implicated mechano-sensory proteins were compared between four cell lines (two from each category). Comparison focused on three levels – that of transmembrane integrins, organization and dynamics of focal adhesions and organization of the actin/myosin cytoskeleton. While increased α₂-integrin levels correlated with rigidity-insensitivity, suppression of activity did not result in rigidity-specific responses, suggesting that integrins provide important growth signals but not in a mechano-sensitive way. In a screen of protein expression, p130Cas and myosin IIC were found to be over-expressed in the rigidityinsensitive cell lines. Interestingly, both proteins show a trend towards decreased expression after growth on soft substrates for 5 days. Further work iii is required to understand the role these proteins play in rigidity responses. Finally, the myosin inhibitor blebbistatin was used to modulate tension in the cells and demonstrated the requirement for myosin activity in all the cell lines regardless of rigidity. Increased cell area in response to short-term blebbistatin treatment correlated with rigidity-insensitive cell lines. One possible explanation is that the rigidity-insensitive cells are under more tension than rigidity-sensitive cells on soft substrates. Taken together, these data indicate multiple levels of dysregulation that could promote growth in the rigidity-insensitive cancer cell lines, independent of extracellular physical cues.

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