Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State

Abstract Cancer cells can acquire a reversible, dormant drug-tolerant persister state mimicking embryonic diapause to evade therapy pressure. Deciphering the precise mechanisms driving cancer cells into or out of a diapause-like persister cell-state could provide strategies to overcome resistance. Here, we showed that following chemotherapy, diverse therapeutic agents converge on WNT pathway activation to induce a de novo diapause-like cell state across various triple-negative breast cancer (TNBC) cell line, xenograft, and patient-derived organoid models. Among early persister cells, only transcriptionally WNT-active persisters exhibited the transcriptional and functional characteristics typical of diapause-like cells, including a negative correlation with MYC transcriptional activity and reversible restricted proliferation. The WNT signaling pathway functioned as both an inducer and biomarker of the diapause-like early persister cell state in both parental (chemo-naïve) and chemotherapy-treated cells. Entry into and exit from the diapause-like early persister cell state was triggered by the transcriptional upregulation of components essential for canonical WNT ligand secretion. A combinatorial treatment strategy inhibiting WNT ligand secretion alongside chemotherapy effectively targeted the early mechanisms underlying the acquisition and enrichment of a diapause-like cell phenotype. These findings reveal WNT pathway activation as an early event that leads to a reversible diapause-like persister state and highlight the potential of targeting this axis to prevent the development of drug-resistant populations before they are firmly established.