FXYD3 functionally demarcates an ancestral breast cancer stem cell subpopulation with features of drug-tolerant persisters

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Abstract
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.
Funding Information
  • Japan Society for the Promotion of Science (JP16H06279（PAGS）)
  • Japan Society for the Promotion of Science (JP16H06277 (CoBiA))
  • Japan Society for the Promotion of Science (JP 18H02679)
  • Japan Society for the Promotion of Science (JP19K22557)
  • Japan Society for the Promotion of Science (JP20H05029)
  • Japan Society for the Promotion of Science (JP21H02761)
  • Japan Agency for Medical Research and Development (19193063)
  • Japan Agency for Medical Research and Development (21446781)

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