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.
Show 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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