Abstract
Cancer cell invasion through physical barriers in the extracellular matrix (ECM) requires a complex synergy of traction force against the ECM, mechanosensitive feedback, and subsequent cytoskeletal rearrangement. PDMS microchannels were used to investigate the transition from mesenchymal to amoeboid invasion in cancer cells. Migration was faster in narrow 3 μm-wide channels than in wider 10 μm channels, even in the absence of cell-binding ECM proteins. Cells permeating narrow channels exhibited blebbing and had smooth leading edge profiles, suggesting an ECM-induced transition from mesenchymal invasion to amoeboid invasion. Live cell labeling revealed a mechanosensing period in which the cell attempts mesenchymal-based migration, reorganizes its cytoskeleton, and proceeds using an amoeboid phenotype. Rho/ROCK (amoeboid) and Rac (mesenchymal) pathway inhibition revealed that amoeboid invasion through confined environments relies on both pathways in a time- and ECM-dependent manner. This demonstrates that cancer cells can dynamically modify their invasion programming to navigate physically confining matrix conditions.
Highlights
Cancer cell invasion is a critical step in primary tumor metastasis
The metastatic process can commence with the invasion of a single cancer cell through narrow confinements in the surrounding extracellular matrix (ECM).[4]
“Pinch-point” assays can follow single-cell behavior by utilizing narrow confinements in which the length of the passage is less than the diameter of a spread cell (∼50 μm).[10,11]
Summary
Rac[1] plays a large role in lamellipodia protrusion and mesenchymal migration.[38,39] ROCK is a downstream effector of RhoA, which promotes stress fiber formation and actomyosin contractile force necessary for blebbing and amoeboid migration.[39,40] Y27632-mediated ROCK inhibition has been shown to prevent the switch from mesenchymal to amoeboid invasion,[41] while inactivation of Rac[1] is sufficient to drive amoeboid movement.[39] We found that both Rac[1] and p160ROCK play a role in self-induced MAT, with Rac[1] responsible for generating initial protrusions into the confined space and the Rho/ROCK pathway providing contractile force necessary for the high cell speeds observed in narrow channels
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