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Modeling the Influence of the E-Cadherin-β-Catenin Pathway in Cancer Cell Invasion: A Multiscale Approach

Ignacio Ramis-Conde ^* , Dirk Drasdo ^* , Alexander R. A. Anderson  and Mark A. J. Chaplain 

^* French National Institute for Research in Computer Science and Control (INRIA), Domaine de Voluceau-Rocquencourt, Le Chesnay, France; Division of Mathematics, The University of Dundee, Dundee, Scotland; and Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, Leipzig, Germany

Correspondence: Address reprint requests to Dirk Drasdo, Tel.: 1-39-63-5036; E-mail: dirk.drasdo{at}inria.fr; and Ignacio Ramis-Conde, ignacio.ramis_conde{at}inria.fr.

In this article, we show, using a mathematical multiscale model, how cell adhesion may be regulated by interactions between E-cadherin and β-catenin and how the control of cell adhesion may be related to cell migration, to the epithelial-mesenchymal transition and to invasion in populations of eukaryotic cells. E-cadherin mediates cell-cell adhesion and plays a critical role in the formation and maintenance of junctional contacts between cells. Loss of E-cadherin-mediated adhesion is a key feature of the epithelial-mesenchymal transition. β-catenin is an intracellular protein associated with the actin cytoskeleton of a cell. E-cadherins bind to β-catenin to form a complex which can interact both with neighboring cells to form bonds, and with the cytoskeleton of the cell. When cells detach from one another, β-catenin is released into the cytoplasm, targeted for degradation, and downregulated. In this process there are multiple protein-complexes involved which interact with β-catenin and E-cadherin. Within a mathematical individual-based multiscale model, we are able to explain experimentally observed patterns solely by a variation of cell-cell adhesive interactions. Implications for cell migration and cancer invasion are also discussed.