Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State.
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ICR Authors
Authors
El Laithy, Y
Abreu De Oliveira, WA
Pabba, A
Qualizza, A
Cosemans, G
Garcia-Diaz, P
Richard, F
Athanasouli, P
Rios Luci, C
De Wispelaere, W
Mourao, L
Hamer, S
Moens, S
De Jaime-Soguero, A
Baietti, MF
Hutten, SJ
Jonkers, J
Sammut, S-J
Soenen, S
Scheele, CLGJ
Bruna, A
Desmedt, C
Annibali, D
Lluis, F
Abreu De Oliveira, WA
Pabba, A
Qualizza, A
Cosemans, G
Garcia-Diaz, P
Richard, F
Athanasouli, P
Rios Luci, C
De Wispelaere, W
Mourao, L
Hamer, S
Moens, S
De Jaime-Soguero, A
Baietti, MF
Hutten, SJ
Jonkers, J
Sammut, S-J
Soenen, S
Scheele, CLGJ
Bruna, A
Desmedt, C
Annibali, D
Lluis, F
Document Type
Journal Article
Date
2026-01-16
Date Accepted
2025-10-10
Abstract
UNLABELLED: 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. In this study, 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 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 (chemotherapy-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. SIGNIFICANCE: WNT signaling is a crucial driver and biomarker of a reversible, dormant, diapause-like persister state in breast cancer cells, offering insights that could transform therapeutic strategies to disrupt tumor persistence.
Citation
Cancer Research, 2026, 86 (2), pp. 310 - 330
Source Title
Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
0008-5472
eISSN
1538-7445
Collections
Research Team
Preclin Paed Cancer Evo
Cancer Dynamics
Cancer Dynamics