Modelling the effect of subcellular mutations on the migration of cells in the colorectal crypt

Abstract

Background: Many cancers arise from mutations in cells within epithelial tissues. Mutations manifesting at the subcellular level influence the structure and function of the tissue resulting in cancer. Previous work has proposed how cell level properties can lead to mutant cell invasion, but has not incorporated detailed subcellular modelling Results: We present a framework that allows the straightforward integration and simulation of SBML representations of subcellular dynamics within multiscale models of epithelial tissues. This allows us to investigate the effect of mutations in subcellular pathways on the migration of cells within the colorectal crypt. Using multiple models we find that mutations in APC, a key component in the Wnt signalling pathway, can bias neutral drift and can also cause downward invasion of mutant cells in the crypt. Conclusions: Our framework allows us to investigate how subcellular mutations, i.e. knockouts and knockdowns, affect cell-level properties and the resultant migration of cells within epithelial tissues. In the context of the colorectal crypt, we see that mutations in APC can lead directly to mutant cell invasion.