ADSL drives fumarate mediated scrib-rictor complex formation to promote metastasis dissemination in triple-negative breast cancer
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BACKGROUND: Triple-negative breast cancer (TNBC) is characterized by aggressive metastatic behavior and limited therapeutic options. Although metabolic reprogramming is increasingly recognized as a hallmark of TNBC, the mechanisms by which specific metabolic enzymes and intermediates drive metastasis remain poorly defined. METHODS: We performed untargeted metabolomic profiling on TNBC tumors and matched normal tissues to identify dysregulated metabolic pathways. Functional assays, chemoproteomic succination profiling, molecular interaction analyses, and in vivo cancer metastasis models were used to define the mechanistic and biological consequences of altered metabolism. In vitro experiments validated the effects of N-acetylcysteine (NAC) in TNBC cell lines. RESULTS: Metabolomic analyses revealed aberrant activation of the alanine-aspartate-glutamate axis and upregulation of adenylosuccinate lyase (ADSL) in TNBC. ADSL promoted tumor cell proliferation and metastasis by generating fumarate, which accumulated primarily through covalent protein succination. Chemoproteomic profiling identified the cell polarity regulator SCRIB as a critical fumarate target. Fumarate-mediated succination of SCRIB impaired its membrane localization, promoted epithelial-mesenchymal transition, and facilitated aberrant interaction with the mTORC2 component RICTOR, leading to activation of AKT/mTOR signaling. Genetic disruption of SCRIB succination abrogated these effects. Importantly, pharmacological perturbation of fumarate using NAC reduced SCRIB succination and attenuated the malignant phenotypes of TNBC cells in vitro. CONCLUSIONS: These findings identify an ADSL-fumarate-SCRIB signaling axis that links metabolic reprogramming to the loss of cell polarity and activation of pro-metastatic signaling in TNBC. Targeting fumarate-mediated protein succination represents a previously unrecognized and experimental vulnerability in TNBC.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- ADSL drives fumarate mediated scrib-rictor complex formation to promote metastasis dissemination in triple-negative breast cancer
- Date Crossref
- 20/07/2026
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Sun Yat-sen University Department of Breast Oncology pays non établi dans la noticeUniversité ou école supérieure
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Sun Yat-sen University Cancer Center pays non établi dans la noticeÉtablissement de santé
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Liaoning Cancer Hospital & Institute pays non établi dans la noticeÉtablissement de santé
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China Medical University pays non établi dans la noticeUniversité ou école supérieure
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Gansu Provincial Hospital pays non établi dans la noticeÉtablissement de santé
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Gansu Provincial Cancer Hospital Gansu Provincial Academic Instiute for Medical Research pays non établi dans la noticeÉtablissement de santé
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Cancer Hospital of Dalian University of Technology Department of General Surgery pays non établi dans la noticeUniversité ou école supérieure
Department of Breast Oncology — Sun Yat-sen University, Sun Yat-sen University Cancer Center et Liaoning Cancer Hospital & Institute, avec 4 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.