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.
Highlights
Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal
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
Our previous theoretical investigations revealed that the core regulatory circuit of epithelial-to-mesenchymal transition (EMT) operates as a three-way switch, allowing for epithelial (E) and mesenchymal (M) phenotypes and for a hybrid epithelial/mesenchymal phenotype (E/M), which is associated with collective cell migration[4,5]
Summary
Bin Huang[1,2], Mingyang Lu1, Mohit Kumar Jolly[1,3], Ilan Tsarfaty[5], Jose Onuchic1,2,4,6 & Eshel Ben-Jacob[1,6,7]. It is widely accepted that deciphering the underlying mechanisms of cellular plasticity during metastatic invasion is central for designing therapeutic targeting of carcinomas[3] To help meet this challenge, we present here theoretical investigations of the GTPase-based operation principles of the Rac1/RhoA circuit - the key regulator for amoeboid-to-mesenchymal transition (AMT). A GTPase protein can switch among its active (GTP-bound state) and inactive (GDP-bound state and GDI-bound state) forms under the regulation of three sets of proteins (GEFs, GAPs and GDIs)[20] Under the assumption that the total level of Rac[1] or RhoA (the sum of levels of GTP-bound, GDP-bound and GDI-bounded form) always reaches a steady state, the above detailed model can be approximated by an effective model (Fig. 2c) described by the following two rate equations
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