CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

Salazar-Roa, M.; G. Martinez-Illescas, N.; Perez-Garcia, G.; Rubert-Hernandez, M.; Quezada-Gutierrez, C.; Martin-Zapater, E.; Alonso-Colmenar, L. M.; Hernandez, C.; Zarco-Cuadrillero, A.; Caleiras, E.; Munoz, M.; Payo-Payo, A.; Frias-Aldeguer, L.; Sanchez, C.; Balcells-Camps, M.; Edelman, E. R.

doi:10.1101/2025.07.29.667375

bioRxiv · 10.1101/2025.07.29.667375

CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

Salazar-Roa, M.·G. Martinez-Illescas, N.·Perez-Garcia, G.·Rubert-Hernandez, M.·Quezada-Gutierrez, C.·Martin-Zapater, E.·Alonso-Colmenar, L. M.·Hernandez, C.·Zarco-Cuadrillero, A.·Caleiras, E.·Munoz, M.·Payo-Payo, A.·Frias-Aldeguer, L.·Sanchez, C.·Balcells-Camps, M.·Edelman, E. R.

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Abstract

Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists--either phytogenic or synthetic--induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress. Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones. Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.

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Salazar-Roa, M., G. Martinez-Illescas, N., Perez-Garcia, G., Rubert-Hernandez, M., Quezada-Gutierrez, C., Martin-Zapater, E., Alonso-Colmenar, L. M., Hernandez, C., Zarco-Cuadrillero, A., Caleiras, E., Munoz, M., Payo-Payo, A., Frias-Aldeguer, L., Sanchez, C., Balcells-Camps, M., Edelman, E. R.. 2025-08-01. CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy. https://doi.org/10.1101/2025.07.29.667375

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