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

• Published in: Nature communications Vol. 10; no. 1; pp. 3668 - 15
• Main Authors: La Belle Flynn, Alyssa, Calhoun, Benjamin C., Sharma, Arishya, Chang, Jenny C., Almasan, Alexandru, Schiemann, William P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.08.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/95; 38; 38/61; 38/89; 42; 6-Phosphofructo-2-kinase; 631/67/1347; 631/67/322; 82/51; 82/80; 96; 96/100; Activation; Animals; Autophagy; Autophagy - genetics; Autophagy-Related Protein 7 - metabolism; Autophagy-Related Proteins - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Self Renewal; Depletion; Disruption; DNA microarrays; Dormancy; Female; Fructose; Gene expression; Humanities and Social Sciences; Humans; Kinases; Lesions; Metastases; Metastasis; Mice; multidisciplinary; Neoplasm Metastasis; Neoplastic Stem Cells - metabolism; Phagocytosis; Phosphofructokinase-2 - metabolism; Science; Science (multidisciplinary); Sequestosome-1 Protein - metabolism; Stem cells; Ubiquitin-Conjugating Enzymes - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11640-9

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. Cancer cells can use autophagy as a mechanism of surviving from external stresses. Here, the authors show that Pfkfb3, a glycolytic gene, is expressed in metastatic breast cancer cells but not in dormant cells that demonstrate features of autophagy.