Sahoo, S and Mishra, A and Kaur, H and Hari, K and Muralidharan, S and Mandal, S and Jolly, MK (2021) A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells. In: NAR Cancer, 3 (3).
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Abstract
Resistance to anti-estrogen therapy is an unsolved clinical challenge in successfully treating ER+ breast cancer patients. Recent studies have demonstrated the role of non-genetic (i.e. phenotypic) adaptations in tolerating drug treatments; however, the mechanisms and dynamics of such non-genetic adaptation remain elusive. Here, we investigate coupled dynamics of epithelial-mesenchymal transition (EMT) in breast cancer cells and emergence of reversible drug resistance. Our mechanism-based model for underlying regulatory network reveals that these two axes can drive one another, thus enabling non-genetic heterogeneity in a cell population by allowing for six co-existing phenotypes: epithelial-sensitive, mesenchymal-resistant, hybrid E/M-sensitive, hybrid E/M-resistant, mesenchymal-sensitive and epithelial-resistant, with the first two ones being most dominant. Next, in a population dynamics framework, we exemplify the implications of phenotypic plasticity (both drug-induced and intrinsic stochastic switching) and/or non-genetic heterogeneity in promoting population survival in a mixture of sensitive and resistant cells, even in the absence of any cell-cell cooperation. Finally, we propose the potential therapeutic use of mesenchymal-epithelial transition inducers besides canonical anti-estrogen therapy to limit the emergence of reversible drug resistance. Our results offer mechanistic insights into empirical observations on EMT and drug resistance and illustrate how such dynamical insights can be exploited for better therapeutic designs. © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.
| Item Type: | Journal Article |
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| Publication: | NAR Cancer |
| Publisher: | Oxford University Press |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | estrogen receptor alpha; tamoxifen, Article; breast cancer cell line; cell plasticity; cell population; cell survival; controlled study; epithelial mesenchymal transition; estrogen receptor positive breast cancer; gene expression; genetic heterogeneity; human; human cell; phenotype; phenotypic plasticity; population dynamics; signal transduction |
| Department/Centre: | Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering UG Programme |
| Date Deposited: | 16 Dec 2022 09:56 |
| Last Modified: | 16 Dec 2022 09:56 |
| URI: | https://eprints.iisc.ac.in/id/eprint/78479 |
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