Chemotherapy-Treated Breast Cancer Cells Activate the WNT Signaling Pathway to Enter a Diapause-Like Early Persister State
Year: 2025
Type: article
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. 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.
Source: Cancer Research
Authors: Youssef El Laithy, Willy Antoni Abreu De Oliveira, Anirudh Pabba, Alessandra Qualizza, Gwenny Cosemans, Paula Garcia-Diaz, François Richard, Paraskevi Athanasouli, Carla Rios Luci, Wout De Wispelaere, Larissa Mourao, Siân Hamer, Stijn Moens, Anchel De Jaime-Soguero, Maria Francesca Baietti, Stefan J. Hutten, Jos Jonkers, Stephen-John Sammut, Stefaan Soenen, Colinda L.G.J. Scheele, Alejandra Bruna, Christine Desmedt, Daniela Annibali, Frederic Lluis
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: Deciphering the molecular mechanism driving cell fate specification during the first lineage decision, Unveiling new molecular mechanisms of therapy-induced adaptive resistance in triple negative breast cancer., G370752126, Unraveling human trophectoderm development with the use of CRISPR/Cas9, Mapping ductal carcinoma in situ in space and time to reveal biomarkers that can predict invasive risk, To co-opt or destroy: Understanding the mechanisms driving replacement or desctructive histological growth patterns in cancer, G7577967522, Unravelling early cell fate decisions during human preimplantation development
OpenAlex ID: W4415376818