Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis

Divya Ramchandani, Mirela Berisa, Diamile A. Tavarez, Zhuoning Li, Matthew Miele, Yang Bai, Sharrell B. Lee, Yi Ban, Noah Dephoure, Ronald C. Hendrickson, Suzanne M. Cloonan, Dingcheng Gao, Justin R. Cross, Linda T. Vahdat () and Vivek Mittal ()
Additional contact information
Divya Ramchandani: Weill Cornell Medicine
Mirela Berisa: Memorial Sloan Kettering Cancer Center
Diamile A. Tavarez: Weill Cornell Medicine
Zhuoning Li: Memorial Sloan Kettering Cancer Center
Matthew Miele: Memorial Sloan Kettering Cancer Center
Yang Bai: Weill Cornell Medicine
Sharrell B. Lee: Weill Cornell Medicine
Yi Ban: Weill Cornell Medicine
Noah Dephoure: Weill Cornell Medicine
Ronald C. Hendrickson: Memorial Sloan Kettering Cancer Center
Suzanne M. Cloonan: Weill Cornell Medicine
Dingcheng Gao: Weill Cornell Medicine
Justin R. Cross: Memorial Sloan Kettering Cancer Center
Linda T. Vahdat: Memorial Sloan Kettering Cancer Center
Vivek Mittal: Weill Cornell Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.

Date: 2021
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DOI: 10.1038/s41467-021-27559-z

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