Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression

Alyssa Flynn, Benjamin C. Calhoun, Arishya Sharma, Jenny C. Chang, Alexandru Almasan and William P. Schiemann ()
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Alyssa Flynn: Department of Pharmacology
Benjamin C. Calhoun: University of North Carolina
Arishya Sharma: Cleveland Clinic
Jenny C. Chang: Houston Methodist Research Center
Alexandru Almasan: Cleveland Clinic
William P. Schiemann: Case Western Reserve University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Breast cancer stem cells (BCSCs) are unique in their ability to undergo unlimited self-renewal, an essential process in breast cancer recurrence following metastatic dormancy. Emergent metastatic lesions were subjected to microarray analysis, which identified 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) as a differentially expressed gene coupled to metastatic recurrence. Here, we report that elevated Pfkfb3 expression correlates with the appearance of aggressive breast cancers and reduces relapse-free survival, as well as enhances BCSC self-renewal and metastatic outgrowth. We observe an inverse relationship between Pfkfb3 expression and autophagy, which reduces Pfkfb3 expression and elicits cellular dormancy. Targeted depletion of Atg3, Atg7, or p62/sequestosome-1 to inactivate autophagy restores aberrant Pfkfb3 expression in dormant BCSCs, leading to their reactivation of proliferative programs and outgrowth. Moreover, Pfkfb3 interacts physically with autophagy machinery, specifically the UBA domain of p62/sequestosome-1. Importantly, disrupting autophagy and this event enables Pfkfb3 to drive dormant BCSCs and metastatic lesions to recur.

Date: 2019
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DOI: 10.1038/s41467-019-11640-9

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