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, Vivek Mittal

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number7311
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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