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.
Mengjiao Li, Tatsunori Nishimura, Yasuto Takeuchi, Tsunaki Hongu, Yuming Wang, Daisuke Shiokawa, Kang Wang, Haruka Hirose, Asako Sasahara, Masao Yano, Satoko Ishikawa, Masafumi Inokuchi, Tetsuo Ota, Masahiko Tanabe, Kei-ichiro Tada, Tetsu Akiyama, Xi Cheng, Chia-Chi Liu, Toshinari Yamashita, Sumio Sugano, Yutaro Uchida, Tomoki Chiba, Hiroshi Asahara, Masahiro Nakagawa, Shinya Sato, Yohei Miyagi, Teppei Shimamura, Luis Augusto E. Nagai, Akinori Kanai, Manami Katoh, Seitaro Nomura, Ryuichiro Nakato, Yutaka Suzuki, Arinobu Tojo, Dominic C. Voon, Seishi Ogawa, Koji Okamoto, Theodoros Foukakis, Noriko Gotoh