TY - JOUR
T1 - Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression
AU - La Belle Flynn, Alyssa
AU - Calhoun, Benjamin C.
AU - Sharma, Arishya
AU - Chang, Jenny C.
AU - Almasan, Alexandru
AU - Schiemann, William P.
N1 - Funding Information:
Members of the Schiemann Laboratory are thanked for critical comments and reading of the manuscript. We also thank Drs. Laura Vera-Ramirez (GENYO), Kent W. Hunter (National Cancer Institute), and Jeffrey E. Green (National Cancer Institute) for providing D2.OR cells that stably expressed the mCherry-EGFP-LC3 reporter construct. We also acknowledge the expertise provided by members of the Case Comprehensive Cancer Center’s Core Facilities, including the Gene Expression & Genotyping Core, the Imaging Research Core, Tissue Resources Core, and the Genomics Core (P30CA043703). Assistance was also provided by the CWRU School of Medicine Light Microscopy Core Facility (S10-RR021228) and by the Cytometry & Imaging Microscopy Core (NH S10OD021559). Research support was provided in part by the National Institutes of Health to W.P.S. (CA177069 and CA236273), A.A. (CA184137), and A.L.B.F. (T32GM008803 and T32CA059366). Additional support was graciously provided by the METAvivor Foundation (W.P.S.), and by pilot funding from the Case Clinical & Translational Science Collaborative (UL1TR000439) and the Case Comprehensive Cancer Center’s Research Innovation Fund, which is supported by the Case Council and Friends of the Case Comprehensive Cancer Center (W.P.S.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/8/14
Y1 - 2019/8/14
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-11640-9
DO - 10.1038/s41467-019-11640-9
M3 - Article
C2 - 31413316
AN - SCOPUS:85070766657
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3668
ER -