posted on 2019-02-18, 00:00authored byAndrew
W. Holle, Neethu Govindan Kutty Devi, Kim Clar, Anthony Fan, Taher Saif, Ralf Kemkemer, Joachim P. Spatz
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.