PXD027089

PXD027089 is an original dataset announced via ProteomeXchange.

Title	Copper depletion modulates OXPHOS in SOX2/OCT4+ cancer cells to impair triple negative breast cancer metastasis.
Description	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 marked sensitivity to TM. Global proteomic and metabolomic profiling identified TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We identified the 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, restricted copper deficiency to mitochondria and phenocopied TM-mediated alterations. These findings identify a novel copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials.
HostingRepository	PRIDE
AnnounceDate	2023-04-11
AnnouncementXML	Submission_2023-04-11_06:14:39.638.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	ZhuoningLi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deaminated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-04 22:58:32	ID requested
1	2021-10-26 07:38:00	announced
⏵ 2	2023-04-11 06:14:40	announced	2023-04-11: Updated project metadata.

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, Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nat Commun, 12(1):7311(2021) [pubmed]

submitter keyword: Metabolism, Mitochondria, Copper, OXPHOS, AMPK, SOX2/OCT4+ cells, Metastasis,Triple negative breast cancer, Tetrathiomolybdate

VivekMittal
contact affiliation	professor of Cardiothoracic Surgery, Cell and Dev Biology Weill Cornell Medicine
contact email	vim2010@mskcc.org
lab head
ZhuoningLi
contact affiliation	MSKCC
contact email	liz2@mskcc.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027089
     1. Label: PRIDE project
     2. Name: Copper depletion modulates OXPHOS in SOX2/OCT4+ cancer cells to impair triple negative breast cancer metastasis.