Translational control of cell plasticity drives 5-FU tolerance

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.