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Matrix adhesion and remodeling diversifies modes of cancer invasion across spatial scales

Pramanik, D and Jolly, MK and Bhat, R (2021) Matrix adhesion and remodeling diversifies modes of cancer invasion across spatial scales. In: Journal of Theoretical Biology, 524 .

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Official URL: https://doi.org/10.1016/j.jtbi.2021.110733


The metastasis of malignant epithelial tumors begins with the egress of transformed cells from the confines of their basement membrane (BM) to their surrounding collagen-rich stroma. Invasion can be morphologically diverse: when breast cancer cells are separately cultured within BM-like matrix, collagen I (Coll I), or a combination of both, they exhibit collective-, dispersed mesenchymal-, and a mixed collective-dispersed (multimodal)- invasion, respectively. In this paper, we asked how distinct these invasive modes are with respect to the cellular and microenvironmental cues that drive them. A rigorous computational exploration of invasion was performed within an experimentally motivated Cellular Potts-based modeling environment. The model comprised of adhesive interactions between cancer cells, BM- and Coll I-like extracellular matrix (ECM), and reaction�diffusion-based remodeling of ECM. The model outputs were parameters cognate to dispersed- and collective- invasion. A clustering analysis of the output distribution curated through a careful examination of subsumed phenotypes suggested at least four distinct invasive states: dispersed, papillary-collective, bulk-collective, and multimodal, in addition to an indolent/non-invasive state. Mapping input values to specific output clusters suggested that each of these invasive states are specified by distinct input signatures of proliferation, adhesion and ECM remodeling. In addition, specific input perturbations allowed transitions between the clusters and revealed the variation in the robustness between the invasive states. Our systems-level approach proffers quantitative insights into how the diversity in ECM microenvironments may steer invasion into diverse phenotypic modes during early dissemination of breast cancer and contributes to tumor heterogeneity. © 2021

Item Type: Journal Article
Publication: Journal of Theoretical Biology
Publisher: Academic Press
Additional Information: The copyright for this article belongs to Authors
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Division of Interdisciplinary Sciences > Interdisciplinary Centre for Energy Research
Date Deposited: 27 Aug 2021 05:58
Last Modified: 27 Aug 2021 05:58
URI: http://eprints.iisc.ac.in/id/eprint/69300

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