Authors
Philippine Bruno, Kübra Özkan, Ophélie Renoult, Maria Virginia Giolito, Sébastien Ibanez, Sarah Srhir, Céline Guilbaud, Florine Laloux, Isabelle Leclercq, Caroline Bouzin, Kristian Serafimov, Chantal Dessy, Léo Aubert, Olivier Feron
Published in
Cell reports. Volume 45. Issue 11. Pages 118261. Nov 06, 2026. Epub Nov 06, 2026.
Abstract
Circadian physiology coordinates systemic and cellular metabolism through a light-entrained central clock and metabolically synchronized peripheral clocks. Whether feeding-fasting cycles or tumor-intrinsic clocks primarily set tumor metabolic state is unclear. Here, we profiled colorectal cancer (CRC) responses to PPAR antagonists across 2D and 3D CRC models and tumor-bearing mice. In standard high-glucose, low-fat medium, Bmal1 oscillations and daily variation in PPAR antagonist sensitivity were apparent in CRC cells. By contrast, nutrient-defined media that recapitulate feeding and nighttime fasting abolished time-dependent variability and unified drug responses across models. Still, the fed state selectively sensitized spheroids and patient-derived organoids to PPAR-γ antagonism. In mice, dosing PPAR-γ antagonist in the fed state prolonged survival and reduced hepatotoxicity. The use of Bmal-1-silenced CRC cells validated that feeding-fasting rhythms, not tumor-intrinsic clocks, govern CRC sensitivity to PPAR antagonists. Our study also supports the predictive capacity of nutrient-alternating 3D tumor models, enabling metabolism-targeted anticancer treatment evaluation.
PMID:
42993626
Bibliographic data and abstract were imported from PubMed on 07 Nov 2026.
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