Session 4 : Molecular mechanisms of resistance

Impact of 5-Fluorouracil on cell plasticity

The 5-Fluorouracil (5-FU), an agent used in all combinations of chemotherapy for colorectal cancer (CRC) as well as in many other cancers, is often associated with resistance and consequently tumor recurrence. Indeed, nearly half of CRC patients experience recurrence within 5 years of their treatment.

Surprisingly, for one of the oldest and most widely used chemotherapies, some aspects of its mode of action remain to be deciphered in detail. Over the past few years, our team in collaboration with Dr. Jean-Jacques Diaz's team at the Lyon Cancer Research Center has revealed the ability of 5-FU to integrate into ribosomal RNA, leading to drastically modified translation. Indeed, ribosomes continue to produce proteins, but only those potentially crucial for cell survival.

We have demonstrated that this modified translation induces cellular reprogramming towards a pluripotent phenotype allowing cells to survive. This study is a proof of concept and only the tip of the iceberg, as single-cell RNA sequencing before and after treatments has revealed the presence of about ten subpopulations.

Our study sheds light on the response and adaptation of cells to 5-FU. These findings highlight the complex nature of cellular responses to 5-FU and could contribute to a deeper understanding of tumor plasticity and treatment resistance.