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Divya Ramchandani, Mirela Berisa, Diamile A. Tavarez, Zhuoning Li, Matthew M. Miele, Yang Bai, Sharrell B. Lee, Yi Ban, Noah Dephoure, Ronald C. Hendrickson and 5 more
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.
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Ramchandani, D., Berisa, M., Tavarez, D. A., Li, Z., Miele, M. 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. (2021). Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nature Communications, 12(1), 7311. https://doi.org/10.1038/s41467-021-27559-z
Ramchandani, Divya, et al. "Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis." Nature Communications, vol. 12, no. 1, 2021, pp. 7311, https://doi.org/10.1038/s41467-021-27559-z.
Ramchandani, Divya, Mirela Berisa, Diamile A. Tavarez, Zhuoning Li, Matthew M. Miele, Yang Bai, Sharrell B. Lee, et al. "Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis." Nature Communications 12, no. 1 (2021): 7311. https://doi.org/10.1038/s41467-021-27559-z.
Ramchandani D., Berisa M., Tavarez D. A. [и др.] Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis // Nature Communications. — 2021. — Vol. 12, № 1. — P. 7311. — URL: https://doi.org/10.1038/s41467-021-27559-z
@article{ramchandani2021copper,
title = {{Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis}},
author = {Divya Ramchandani and Mirela Berisa and Diamile A. Tavarez and Zhuoning Li and Matthew M. Miele and Yang Bai and Sharrell B. Lee and Yi Ban and Noah Dephoure and Ronald C. Hendrickson and Suzanne M. Cloonan and Dingcheng Gao and Justin R. Cross and Linda T. Vahdat and Vivek Mittal},
journal = {Nature Communications},
year = {2021},
volume = {12},
number = {1},
pages = {7311},
doi = {10.1038/s41467-021-27559-z},
url = {https://doi.org/10.1038/s41467-021-27559-z}
}TY - JOUR AU - Ramchandani, Divya AU - Berisa, Mirela AU - Tavarez, Diamile A. AU - Li, Zhuoning AU - Miele, Matthew M. AU - Bai, Yang AU - Lee, Sharrell B. AU - Ban, Yi AU - Dephoure, Noah AU - Hendrickson, Ronald C. AU - Cloonan, Suzanne M. AU - Gao, Dingcheng AU - Cross, Justin R. AU - Vahdat, Linda T. AU - Mittal, Vivek TI - Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis JO - Nature Communications VL - 12 IS - 1 SP - 7311 PY - 2021 DA - 2021/12/15 DO - 10.1038/s41467-021-27559-z UR - https://doi.org/10.1038/s41467-021-27559-z ER -
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