The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition

Abstract

Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of, and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

“…Because EMT is no longer considered to be a binary process [6,57,58], and stemness is being understood as a reversible trait of cells rather than their fixed state [59], such multistability, as also observed during transitions between amoeboid and mesenchymal phenotypes [60], might be used by cancer cells to adapt to their changing microenvironments.…”

Multiple mechanisms of 3D migration: the origins of plasticity

“…But why do these cells not continue to migrate using lamellipodia? One possibility is that elevated RhoA simply shuts off Rac1 signaling and lamellipodia formation through classical RhoA-Rac1 biochemical crosstalk [45,61]. Alternatively, membrane tension may be significantly elevated in high-pressure cells due to pushing of the cytoplasm against the plasma membrane.…”

Computational modeling of single‐cell mechanics and cytoskeletal mechanobiology

“…While molecular interrogation has yielded extensive insights into the processes responsible for reorganization of the cytoskeleton during migration, one of the major challenges still to be addressed is to understand how these biophysical processes and their control contribute to broader morphology and migratory behavior of cells. In the context of migration, cells can exhibit different sensitivities to stimuli, different levels of persistence, and even different types of migration (amoeboid versus mesenchymal) . Modeling has provided numerous insights into how various actin binding proteins interact with the cytoskeleton, and how the actions of those proteins coordinate different types of force production.…”