An Interplay Between Reaction-Diffusion and Cell-Matrix Adhesion Regulates Multiscale Invasion in Early Breast Carcinomatosis

Pally, Dharma and Pramanik, Durjay and Bhat, Ramray (2019) An Interplay Between Reaction-Diffusion and Cell-Matrix Adhesion Regulates Multiscale Invasion in Early Breast Carcinomatosis. In: FRONTIERS IN PHYSIOLOGY, 10 .

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Abstract

The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodeled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale three-dimensional (3D) organo- and pathotypic experimental assay that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End point and time-lapse microscopic observations of this assay allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then simulate our experimental observations using the modeling environment Compucell3D that is based on the Glazier-Graner-Hogeweg model. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Further parametric exploration-based simulations suggest that specific permissive regimes of cell-cell and cell-matrix adhesions, operating in the context of a reaction-diffusion-regulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which the latter migrate through their surrounding stroma.

Item Type:	Journal Article
Publication:	FRONTIERS IN PHYSIOLOGY
Publisher:	FRONTIERS MEDIA SA
Additional Information:	copyright for this article belongs to FRONTIERS MEDIA SA
Keywords:	breast cancer; multiscale invasion; cell adhesion; reaction diffusion; cellular potts model (CPM)
Department/Centre:	Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited:	18 Sep 2019 10:51
Last Modified:	18 Sep 2019 10:51
URI:	http://eprints.iisc.ac.in/id/eprint/63517

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