Age-dependent chemotherapy response and vitamin D impact in paired patient-derived normal and tumor colorectal organoids

Fernandez-Barral, A.; Barbachano, A.; Rodriguez-Marrero, S.; del Peso, L.; Herreros-Cabello, A.; Rodriguez-Salas, N.; Prieto, I.; Burgos, A.; Leon-Arellano, M.; Garcia-Olmo, D.; Olleros, T.; Gonzalez-Sancho, J. M.; Larriba, M. J.; Munoz, A.

doi:10.64898/2025.12.15.694334

bioRxiv · 10.64898/2025.12.15.694334

Age-dependent chemotherapy response and vitamin D impact in paired patient-derived normal and tumor colorectal organoids

Fernandez-Barral, A.·Barbachano, A.·Rodriguez-Marrero, S.·del Peso, L.·Herreros-Cabello, A.·Rodriguez-Salas, N.·Prieto, I.·Burgos, A.·Leon-Arellano, M.·Garcia-Olmo, D.·Olleros, T.·Gonzalez-Sancho, J. M.·Larriba, M. J.·Munoz, A.

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Abstract

Early-onset colorectal cancer (EO-CRC, <50 years) incidence is rising worldwide. Using paired patient-derived colorectal normal and tumor organoids, we demonstrate the therapeutic window of three standard chemotherapies. Normal organoids were more resistant than tumor organoids to 5-fluorouracil (5-FU) and oxaliplatin in both EO-CRC and late-onset CRC (LO-CRC) patients. However, for SN38, this therapeutic window was observed in LO-CRC but not in EO-CRC patients, revealing age-dependent differences in drug resistance. We also evaluated the effect of calcitriol, the active vitamin D metabolite with anti-CRC activity, on drug sensitivity. Calcitriol reduced the cytotoxicity of 5-FU and SN38 in normal organoids regardless of patient age, while it selectively decreased their cytotoxicity in EO-CRC but not in LO-CRC tumor organoids. This protective effect correlated with calcitriol antiproliferative action and transcriptional effects on drug-metabolism pathways. These findings identify clinically relevant age-dependent differences in chemotherapy response and support vitamin D-based strategies to design age-tailored precision treatments.

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Fernandez-Barral, A., Barbachano, A., Rodriguez-Marrero, S., del Peso, L., Herreros-Cabello, A., Rodriguez-Salas, N., Prieto, I., Burgos, A., Leon-Arellano, M., Garcia-Olmo, D., Olleros, T., Gonzalez-Sancho, J. M., Larriba, M. J., Munoz, A.. 2025-12-17. Age-dependent chemotherapy response and vitamin D impact in paired patient-derived normal and tumor colorectal organoids. https://doi.org/10.64898/2025.12.15.694334

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