Modelling GTPase dynamics to understand RhoA-driven cancer cell invasion

Biochem Soc Trans. 2016 Dec 15;44(6):1695-1700. doi: 10.1042/BST20160184.

Abstract

Metastasis, initially driven by cells migrating and invading through the local environment, leads to most cancer-associated deaths. Cells can use a variety of modes to move in vitro, all of which depend on Rho GTPases at some level. While traditionally it was thought that Rac1 activity drives protrusive lamellipodia at the leading edge of a polarised cell while RhoA drives rear retraction, more recent work in 3D microenvironments has revealed a much more complicated picture of GTPase dynamics. In particular, RhoA activity can dominate the leading edge polymerisation of actin to form filopodial actin-spike protrusions that drive more invasive cell migration. We recently described a potential mechanism to abrogate this pro-invasive localised leading edge Rac1 to RhoA switch via manipulation of a negative feedback loop that was revealed by adopting a logical modelling approach. Both challenging dogma and taking a formal, mathematical approach to understanding signalling involved in motility may be vital to harnessing harmful cell migration and preventing metastasis in future research.

Keywords: Boolean logic; RhoA; biological networks; cell migration; filopodia.

MeSH terms

  • Cell Movement*
  • ErbB Receptors / metabolism
  • Extracellular Matrix / metabolism
  • Humans
  • Models, Biological*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Pseudopodia / metabolism
  • Signal Transduction
  • rho GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • ErbB Receptors
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein