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Multi-stability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells

Chedere, A and Hari, K and Kumar, S and Rangarajan, A and Jolly, MK (2021) Multi-stability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells. In: Journal of Clinical Medicine, 10 (3). pp. 1-16.

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Official URL: https://doi.org/10.3390/jcm10030472


Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK (AMP-activated protein kinase) and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can significantly generate two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlow state, and matrix (re)attachment-triggered pAkthigh/ pAMPKlow state. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism- based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlow and pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB- 231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of The Cancer Genome Atlas (TCGA) breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPKAkt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population.

Item Type: Journal Article
Publication: Journal of Clinical Medicine
Publisher: MDPI
Additional Information: The copyright for this article belongs to the Authors.
Keywords: protein kinase B; protein serine threonine kinase, Article; breast cancer; cancer cell; cell communication; clinical study; feedback system; human; human cell; kinetic parameters; mathematical model; negative feedback; phenotype; phenotypic plasticity; sensitivity analysis
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering
Date Deposited: 22 May 2023 04:09
Last Modified: 22 May 2023 04:09
URI: https://eprints.iisc.ac.in/id/eprint/81708

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