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A Non-genetic Mechanism Involving the Integrin β4/Paxillin Axis Contributes to Chemoresistance in Lung Cancer

Mohanty, A and Nam, A and Pozhitkov, A and Yang, L and Srivastava, S and Nathan, A and Wu, X and Mambetsariev, I and Nelson, M and Subbalakshmi, AR and Guo, L and Nasser, MW and Batra, SK and Orban, J and Jolly, MK and Massarelli, E and Kulkarni, P and Salgia, R (2020) A Non-genetic Mechanism Involving the Integrin β4/Paxillin Axis Contributes to Chemoresistance in Lung Cancer. In: iScience, 23 (9).

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Official URL: https://dx.doi.org/10.1016/j.isci.2020.101496


Cell Biology; Mathematical Biosciences; Cancer © 2020 The Authors Tumor heterogeneity and cisplatin resistance are major causes of tumor relapse and poor survival. Here, we show that in lung cancer, interaction between paxillin (PXN) and integrin β4 (ITGB4), components of the focal adhesion (FA) complex, contributes to cisplatin resistance. Knocking down PXN and ITGB4 attenuated cell growth and improved cisplatin sensitivity, both in 2D and 3D cultures. PXN and ITGB4 independently regulated expression of several genes. In addition, they also regulated expression of common genes including USP1 and VDAC1, which are required for maintaining genomic stability and mitochondrial function, respectively. Mathematical modeling suggested that bistability could lead to stochastic phenotypic switching between cisplatin-sensitive and resistant states in these cells. Consistently, purified subpopulations of sensitive and resistant cells re-created the mixed parental population when cultured separately. Altogether, these data point to an unexpected role of the FA complex in cisplatin resistance and highlight a novel non-genetic mechanism. © 2020 The Authors

Item Type: Journal Article
Publication: iScience
Publisher: Elsevier Inc.
Additional Information: Copyright belongs to the authors.
Department/Centre: Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 13 Mar 2021 09:10
Last Modified: 13 Mar 2021 09:10
URI: http://eprints.iisc.ac.in/id/eprint/66749

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