Spatial heterogeneity in tumor adhesion qualifies collective cell invasion

Prasanna, CVS and Jolly, MK and Bhat, R (2024) Spatial heterogeneity in tumor adhesion qualifies collective cell invasion. In: Biophysical Journal, 123 (12). pp. 1635-1647.

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Abstract

Collective cell invasion (CCI), a canon of most invasive solid tumors, is an emergent property of the interactions between cancer cells and their surrounding extracellular matrix (ECM). However, tumor populations invariably consist of cells expressing variable levels of adhesive proteins that mediate such interactions, disallowing an intuitive understanding of how tumor invasiveness at a multicellular scale is influenced by spatial heterogeneity of cell-cell and cell-ECM adhesion. Here, we have used a Cellular Potts model-based multiscale computational framework that is constructed on the histopathological principles of glandular cancers. In earlier efforts on homogenous cancer cell populations, this framework revealed the relative ranges of interactions, including cell-cell and cell-ECM adhesion that drove collective, dispersed, and mixed multimodal invasion. Here, we constitute a tumor core of two separate cell subsets showing distinct intra- and inter-subset cell-cell or cell-ECM adhesion strengths. These two subsets of cells are arranged to varying extents of spatial intermingling, which we call the heterogeneity index (HI). We observe that low and high inter-subset cell adhesion favors invasion of high-HI and low-HI intermingled populations with distinct intra-subset cell-cell adhesion strengths, respectively. In addition, for explored values of cell-ECM adhesion strengths, populations with high HI values collectively invade better than those with lower HI values. We then asked how spatial invasion is regulated by progressively intermingled cellular subsets that are epithelial, i.e., showed high cell-cell but poor cell-ECM adhesion, and mesenchymal, i.e., with reversed adhesion strengths to the former. Here too, inter-subset adhesion plays an important role in contextualizing the proportionate relationship between HI and invasion. An exception to this relationship is seen for cases of heterogeneous cell-ECM adhesion where sub-maximal HI patterns with higher outer localization of cells with stronger ECM adhesion collectively invade better than their relatively higher-HI counterparts. Our simulations also reveal how adhesion heterogeneity qualifies collective invasion, when either cell-cell or cell-ECM adhesion type is varied but results in an invasive dispersion when both adhesion types are simultaneously altered. © 2024 Biophysical Society

Item Type:	Journal Article
Publication:	Biophysical Journal
Publisher:	Biophysical Society
Additional Information:	The copyright for this article belongs to Biophysical Society.
Department/Centre:	Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering Division of Interdisciplinary Sciences > Interdisciplinary Mathematical Sciences
Date Deposited:	12 Aug 2024 11:11
Last Modified:	12 Aug 2024 11:11
URI:	http://eprints.iisc.ac.in/id/eprint/85267

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