Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Yining Cai  

LAB HEAD: Johannes F. Fahrmann

PROVIDER: PXD068183 | Pride | 2025-09-30

REPOSITORIES: Pride