FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters.
Breast cancer
Drug therapy
Oncology
Stem cells
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
15 Nov 2023
15 Nov 2023
Historique:
received:
08
11
2022
accepted:
21
09
2023
medline:
16
11
2023
pubmed:
15
11
2023
entrez:
15
11
2023
Statut:
epublish
Résumé
The heterogeneity of cancer stem cells (CSCs) within tumors presents a challenge in therapeutic targeting. To decipher the cellular plasticity that fuels phenotypic heterogeneity, we undertook single-cell transcriptomics analysis in triple-negative breast cancer (TNBC) to identify subpopulations in CSCs. We found a subpopulation of CSCs with ancestral features that is marked by FXYD domain-containing ion transport regulator 3 (FXYD3), a component of the Na+/K+ pump. Accordingly, FXYD3+ CSCs evolve and proliferate, while displaying traits of alveolar progenitors that are normally induced during pregnancy. Clinically, FXYD3+ CSCs were persistent during neoadjuvant chemotherapy, hence linking them to drug-tolerant persisters (DTPs) and identifying them as crucial therapeutic targets. Importantly, FXYD3+ CSCs were sensitive to senolytic Na+/K+ pump inhibitors, such as cardiac glycosides. Together, our data indicate that FXYD3+ CSCs with ancestral features are drivers of plasticity and chemoresistance in TNBC. Targeting the Na+/K+ pump could be an effective strategy to eliminate CSCs with ancestral and DTP features that could improve TNBC prognosis.
Identifiants
pubmed: 37966117
pii: 166666
doi: 10.1172/JCI166666
pmc: PMC10645391
doi:
pii:
Substances chimiques
FXYD3 protein, human
0
Membrane Proteins
0
Neoplasm Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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