Vesicle-Mediated Mitochondrial Clearance Presents an Actionable Metabolic Vulnerability in Triple-Negative Breast Cancer

Authors

Jody Vykoukal
Yihui Chen
Mingxin Zuo
Riccardo Ballarò
Monica J Hong
Hansini Krishna
Daniela B Rodriquez-Perera
Hiroyuki Katayama
Ehsan Irajizad
Ranran Wu
Ricardo A León-Letelier
Jennifer B Dennison
Angelica M Gutierrez
Adriana Paulucci-Holthauzen
Timothy C Thompson
Leona Rusling
Yining Cai
Fu Chung Hsiao
Soyoung Park
Banu Arun
Samir Hanash
Johannes F Fahrmann

Language

English

Publication Date

12-16-2025

Journal

Cell Reports Medicine

DOI

10.1016/j.xcrm.2025.102478

PMID

41406946

PMCID

PMC12765847

PubMedCentral® Posted Date

12-16-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death in vitro and attenuates tumor growth and prolongs overall survival at clinically achievable doses in orthotopic syngeneic mouse models of TNBC as well as in human cell line-derived xenograft models. Our study defines an unexplored mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

Keywords

Triple Negative Breast Neoplasms, Humans, Mitochondria, Animals, Female, Cell Line, Tumor, Mice, Mitophagy, Xenograft Model Antitumor Assays, Ceramides, Extracellular Vesicles, Sphingomyelins, Autophagy, Glucosyltransferases, sphingolipids, mitochondria, autophagy, extracellular vesicles, triple-negative breast cancer, glucosylceramide synthase, eliglustat

Published Open-Access

yes

Recommended Citation

Vykoukal, Jody; Chen, Yihui; Zuo, Mingxin; et al., "Vesicle-Mediated Mitochondrial Clearance Presents an Actionable Metabolic Vulnerability in Triple-Negative Breast Cancer" (2025). Faculty, Staff and Student Publications. 5301.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5301