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

170 Scopus citations

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
Pages (from-to)7311
JournalNature Communications
Volume12
Issue number1
DOIs
StatePublished - Dec 15 2021

Keywords

  • Animals
  • Cell Line, Tumor
  • Copper/metabolism
  • Copper Transport Proteins/genetics
  • Female
  • Humans
  • Mechanistic Target of Rapamycin Complex 1/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria/genetics
  • Neoplasm Metastasis
  • Octamer Transcription Factor-3/genetics
  • Oxidative Phosphorylation
  • SOXB1 Transcription Factors/genetics
  • Triple Negative Breast Neoplasms/genetics

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis'. Together they form a unique fingerprint.

Cite this