Chemotherapy-treated breast cancer cells activate the Wnt signaling pathway to enter a diapause-DTP state

ABSTRACT The efficacy of chemotherapy is often hindered by the enrichment of a population of cancer cells that enter a drug-tolerant persister (DTP) state, mimicking embryonic diapause, yet the underlying mechanisms of this transition remain poorly understood. This study demonstrates that both parental and chemotherapy-induced Wnt-active (Wnt High ) cells in Triple-negative breast cancer exhibit transcriptional and functional properties characteristic of DTP cells, including a diapause transcriptional signature, reduced MYC expression, reversible restricted proliferation, and pronounced chemoresistance. Our findings reveal that the de novo activation of the Wnt signaling pathway, triggered by the transcriptional upregulation of components essential for canonical Wnt ligand-secretion and -activation, is critical for enriching the diapause-DTP (DTP Diap ) population across various chemotherapy regimens. The diapause-DTP/Wnt High population can be selectively ablated by concomitant, rather than sequential, pharmacological inhibition of Wnt ligand-secretion alongside chemotherapy, highlighting new vulnerabilities in DTP Diap cell-emergence and potentially yielding a therapeutic opportunity against DTPs. This study shows that activation of Wnt signaling pathway is sufficient and necessary for the induction of a DTP Diap state and enhances our understanding of the introductory mechanisms driving DTP cell-enrichment upon chemotherapy.