American Association for Cancer Research
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Supplementary Figure Legends and Materials from AMPK–Akt Double-Negative Feedback Loop in Breast Cancer Cells Regulates Their Adaptation to Matrix Deprivation

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journal contribution
posted on 2023-03-31, 01:22 authored by Manipa Saha, Saurav Kumar, Shoiab Bukhari, Sai A. Balaji, Prashant Kumar, Sravanth K. Hindupur, Annapoorni Rangarajan

File contains figure legends for supplementary figure and method and material


Wellcome Trust/DBT India Alliance


UGC, Government of India



Cell detachment from the extracellular matrix triggers anoikis. Disseminated tumor cells must adapt to survive matrix deprivation, while still retaining the ability to attach at secondary sites and reinitiate cell division. In this study, we elucidate mechanisms that enable reversible matrix attachment by breast cancer cells. Matrix deprival triggered AMPK activity and concomitantly inhibited AKT activity by upregulating the Akt phosphatase PHLPP2. The resultant pAMPKhigh/pAktlow state was critical for cell survival in suspension, as PHLPP2 silencing also increased anoikis while impairing autophagy and metastasis. In contrast, matrix reattachment led to Akt-mediated AMPK inactivation via PP2C-α-mediated restoration of the pAkthigh/pAMPKlow state. Clinical specimens of primary and metastatic breast cancer displayed an Akt-associated gene expression signature, whereas circulating breast tumor cells displayed an elevated AMPK-dependent gene expression signature. Our work establishes a double-negative feedback loop between Akt and AMPK to control the switch between matrix-attached and matrix-detached states needed to coordinate cell growth and survival during metastasis.Significance: These findings reveal a molecular switch that regulates cancer cell survival during metastatic dissemination, with the potential to identify targets to prevent metastasis in breast cancer. Cancer Res; 78(6); 1497–510. ©2018 AACR.