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 language | English (US) |
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Article number | 7311 |
Pages (from-to) | 7311 |
Journal | Nature Communications |
Volume | 12 |
Issue number | 1 |
DOIs | |
State | Published - 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