PXD068183-1

PXD068183 is an original dataset announced via ProteomeXchange.

Title	Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer
Description	Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies, including triple-negative breast cancer (TNBC). Here, we investigate the essential metabolic adaptations that support mitochondrial quality control in cancer cells with the aim to uncover therapeutically actionable metabolic vulnerabilities. Using TNBC as a model system and an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, together with functional experimental analyses, we detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of this sphingolipid pathway in cancer cells via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-mediated compensatory mitophagy and subsequent cancer cell death in vitro and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse models of TNBC as well as in human cell-line derived xenograft models. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.
HostingRepository	PRIDE
AnnounceDate	2025-09-30
AnnouncementXML	Submission_2025-09-30_08:02:25.101.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yining Cai
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Bruker Daltonics timsTOF series

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-08 07:30:59	ID requested
⏵ 1	2025-09-30 08:02:25	announced

Dataset with its publication pending

submitter keyword: Sphingolipids

Mitochondria

Autophagy

Extracellular Vesicles

Triple Negative Breast Cancer

Johannes F. Fahrmann
contact affiliation	Assistant Professor, Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center
contact email	JFFahrmann@mdanderson.org
lab head
Yining Cai
contact affiliation	Software Developer
contact email	ycai4@mdanderson.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD068183
     1. Label: PRIDE project
     2. Name: Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer