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Translational control of cell plasticity drives 5-FU tolerance

CHALABI-DCHAR, M.; VILLERONCE, O.; RIPOLL, J.; VINCENT, A.; FENOUIL, T.; KHOUEIRY, R.; KUCHARCZAK, J.; JENTSCHEL, L.; CATEZ, F.; Vigneron, A. M.; TREGUIER, J.; MANDIER, C.; BOUCLIER, C.; VITRE, J.; LAGERQVIST, L.; CHOQUET, A.; HERCEG, Z.; MACHON, C.; GUITTON, J.; DAVID, A.; SOLARY, E.; Bernard, D.; MARTIN, N.; RIVALS, E.; DALLA VENEZIA, N.; Pannequin, J.; DIAZ, J.-J.

2024-07-06 cancer biology
10.1101/2024.07.03.601826 bioRxiv
Show abstract

All routine clinical treatments for colorectal cancer include 5-fluorouracil (5-FU), which cannot counteract recurrence and metastases formation. As the pyrimidine analog 5-FU can impact multiple pathways including both DNA and RNA metabolism, studying its mode of actions could lead to improved therapies. Using a dedicated reporter system for lineage-tracing and deep translatome profiling we demonstrate that 5-FU causes some colorectal cancer cells to tolerate the drug, due to a durable translational reprogramming that sustains cell plasticity. This period of drug tolerance coincides with specific translational activation of genes coding for proteins with major pro-tumoral functions. We unravel a major unexpected translational overexpression of the pro-inflammatory and pro-tumoral IL-8 cytokine, alongside other anti-apoptotic, senescence-associated secretory phenotype and cancer-related senescence phenotype genes. Given the adverse prognostic implications of elevated IL-8 levels across various cancers, our findings suggest IL-8 targeting could counteract 5-FU resistance.

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