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

Divya Ramchandani,Noah Dephoure,Zhuoning Li,Matthew Miele,Yang Bai,Vivek Mittal,Suzanne M Cloonan,Dingcheng Gao,Justin R Cross,Diamile A Tavarez,Linda T Vahdat,Sharrell B Lee,Mirela Berisa,Ronald C Hendrickson,Yi Ban

doi:10.1038/s41467-021-27559-z

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.

Highlights

Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression
TM treatment effectively reduced disseminated tumor cells in early lungs as determined by flow cytometry analysis (Fig. 4g). These results suggest that copper depletion-mediated reduction in oxidative phosphorylation (OXPHOS) impairs invasion in vitro and targets a specific population of metastatic tumor cells in vivo and that TM targets a subpopulation of metastatic tumor cells that rely on OXPHOS
Copper depletion has emerged as a viable cancer therapeutic approach in breast cancer due to increased cellular uptake by malignant cancer cells and reliance on copper-dependent signaling pathways[11,54,55]

Summary

Introduction

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. 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. Metals function as co-factors for a host of metalloenzymes/proteins that contribute to tumor growth and metastasis and targeting metals to disable these pathways has emerged as a potential anti-cancer therapeutic strategy[3,4]. Advancing TM into larger randomized phase II trials will be facilitated by a better understanding of the mechanisms by which copper depletion impacts metastasis and may inform patient selection for future trials

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Conclusion