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

doi:10.1038/s41467-021-27559-z

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 journal › Article › peer-review

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)
Article number	7311
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27559-z
State	Published - Dec 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-27559-z

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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. (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

Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. / Ramchandani, Divya; Berisa, Mirela; Tavarez, Diamile A.; Li, Zhuoning; Miele, Matthew; Bai, Yang; Lee, Sharrell B.; Ban, Yi; Dephoure, Noah; Hendrickson, Ronald C.; Cloonan, Suzanne M.; Gao, Dingcheng; Cross, Justin R.; Vahdat, Linda T.; Mittal, Vivek.

In: Nature Communications, Vol. 12, No. 1, 7311, 12.2021.

Research output: Contribution to journal › Article › peer-review

Ramchandani, D, Berisa, M, Tavarez, DA, Li, Z, Miele, M, Bai, Y, Lee, SB, Ban, Y, Dephoure, N, Hendrickson, RC, Cloonan, SM, Gao, D, Cross, JR, Vahdat, LT & Mittal, V 2021, 'Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis', Nature Communications, vol. 12, no. 1, 7311. https://doi.org/10.1038/s41467-021-27559-z

Ramchandani, Divya ; Berisa, Mirela ; Tavarez, Diamile A. ; Li, Zhuoning ; Miele, Matthew ; Bai, Yang ; Lee, Sharrell B. ; Ban, Yi ; Dephoure, Noah ; Hendrickson, Ronald C. ; Cloonan, Suzanne M. ; Gao, Dingcheng ; Cross, Justin R. ; Vahdat, Linda T. ; Mittal, Vivek. / Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. In: Nature Communications. 2021 ; Vol. 12, No. 1.

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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.",

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

note = "Funding Information: We thank Drs. Tim McGraw and John Blenis for advice. We also thank Elizabeth Perez for technical support. The work described was partly supported by the Center on the Physics of Cancer Metabolism through Award Number U54CA210184 from the National Cancer Institute. This work was also supported by NCI award R01 CA257254-01A1 (V.M. and L.T.V.). Additional funding was provided by the Berman Fund, Subaru Share the Love Campaign (Bay Ridge Subaru), Pisani Family Fund, Anonymous Donor and TM patients, family and friends. We thank David and Rory Jones for their generous support. We also thank Lattner Foundation and Pablo Spiller. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

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doi = "10.1038/s41467-021-27559-z",

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AU - Berisa, Mirela

AU - Tavarez, Diamile A.

AU - Li, Zhuoning

AU - Miele, Matthew

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

N1 - Funding Information: We thank Drs. Tim McGraw and John Blenis for advice. We also thank Elizabeth Perez for technical support. The work described was partly supported by the Center on the Physics of Cancer Metabolism through Award Number U54CA210184 from the National Cancer Institute. This work was also supported by NCI award R01 CA257254-01A1 (V.M. and L.T.V.). Additional funding was provided by the Berman Fund, Subaru Share the Love Campaign (Bay Ridge Subaru), Pisani Family Fund, Anonymous Donor and TM patients, family and friends. We thank David and Rory Jones for their generous support. We also thank Lattner Foundation and Pablo Spiller. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - 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.

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

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