Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis Journal Article
| Authors: | Ramchandani, D.; Berisa, M.; Tavarez, D. A.; Li, Z.; Miele, M.; Bai, Y.; Lee, S. B.; Ban, Y.; Dephoure, N.; Hendrickson, R. C.; Cloonan, S. M.; Gao, D.; Cross, J. R.; Vahdat, L. T.; Mittal, V. |
| Article Title: | Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis |
| 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. © 2021, The Author(s). |
| Keywords: | metabolism; protein; proteomics; tumor; mitochondrion; copper; chemical reaction; inhibition; subpopulation; chelating agent; detection method; cancer |
| Journal Title: | Nature Communications |
| Volume: | 12 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-12-15 |
| Start Page: | 7311 |
| Language: | English |
| DOI: | 10.1038/s41467-021-27559-z |
| PROVIDER: | scopus |
| PMCID: | PMC8674260 |
| PUBMED: | 34911956 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 January 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work