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Erratum: Iyer, A., et al. Integrative Analysis and Machine Learning Based Characterization of Single Circulating Tumor Cells. J. Clin. Med. 2020, 9, 1206
Article

Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells

1
Department of Molecular Reproduction, Development, and Genetics, Indian Institute of Science, Bangalore 560012, India
2
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
3
Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Emmanuel Andrès
J. Clin. Med. 2021, 10(3), 472; https://doi.org/10.3390/jcm10030472
Received: 21 December 2020 / Revised: 7 January 2021 / Accepted: 21 January 2021 / Published: 26 January 2021
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 AMPK-Akt feedback loop can generate multi-stability and drive phenotypic switching and heterogeneity in a cancer cell population. View Full-Text
Keywords: phenotypic plasticity; bistability; double negative feedback loop; AMPK; Akt; matrix deprivation; anchorage independence phenotypic plasticity; bistability; double negative feedback loop; AMPK; Akt; matrix deprivation; anchorage independence
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MDPI and ACS Style

Chedere, A.; Hari, K.; Kumar, S.; Rangarajan, A.; Jolly, M.K. Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells. J. Clin. Med. 2021, 10, 472. https://doi.org/10.3390/jcm10030472

AMA Style

Chedere A, Hari K, Kumar S, Rangarajan A, Jolly MK. Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells. Journal of Clinical Medicine. 2021; 10(3):472. https://doi.org/10.3390/jcm10030472

Chicago/Turabian Style

Chedere, Adithya, Kishore Hari, Saurav Kumar, Annapoorni Rangarajan, and Mohit K. Jolly. 2021. "Multi-Stability and Consequent Phenotypic Plasticity in AMPK-Akt Double Negative Feedback Loop in Cancer Cells" Journal of Clinical Medicine 10, no. 3: 472. https://doi.org/10.3390/jcm10030472

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