RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
15
02
2023
accepted:
07
07
2023
revised:
29
06
2023
medline:
28
8
2023
pubmed:
20
7
2023
entrez:
19
7
2023
Statut:
ppublish
Résumé
Epithelial/Mesenchymal (E/M) plasticity plays a fundamental role both in embryogenesis and during tumorigenesis. The receptor for advanced glycation end products (RAGE) is a driver of cell plasticity in fibrotic diseases; however, its role and molecular mechanism in triple-negative breast cancer (TNBC) remains unclear. Here, we demonstrate that RAGE signaling maintains the mesenchymal phenotype of aggressive TNBC cells by enforcing the expression of SNAIL1. Besides, we uncover a crosstalk mechanism between the TGF-β and RAGE pathways that is required for the acquisition of mesenchymal traits in TNBC cells. Consistently, RAGE inhibition elicits epithelial features that block migration and invasion capacities. Next, since RAGE is a sensor of the tumor microenvironment, we modeled acute acidosis in TNBC cells and showed it promotes enhanced production of RAGE ligands and the activation of RAGE-dependent invasive properties. Furthermore, acute acidosis increases SNAIL1 levels and tumor cell invasion in a RAGE-dependent manner. Finally, we demonstrate that in vivo inhibition of RAGE reduces metastasis incidence and expands survival, consistent with molecular effects that support the relevance of RAGE signaling in E/M plasticity. These results uncover new molecular insights on the regulation of E/M phenotypes in cancer metastasis and provide rationale for pharmacological intervention of this signaling axis.
Identifiants
pubmed: 37468678
doi: 10.1038/s41388-023-02778-4
pii: 10.1038/s41388-023-02778-4
doi:
Substances chimiques
Receptor for Advanced Glycation End Products
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2610-2628Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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