De rol van de rRNA-modificaties en lncRNA-afgeleide micropeptiden bij herbedrading van melanoom translatie en therapieresistentie

In metastatic melanoma, despite the recent breakthroughs in targeted therapy and Immune Checkpoint Blockade (ICB), the 5-year survival rate remains around 54%. This is at least in part due to the high plasticity of melanoma cells and their ability to quickly switch between different drug-tolerant states upon therapy exposure, allowing them to escape this threat. Phenotype switching into an undifferentiated drug-tolerant state can be induced in vitro by activating the Integrative Stress Response (ISR), an adaptive program triggered by several intracellular and extracellular stressors, leading to a decrease in global translation alongside with the synthesis of selected proteins important for survival. Our lab recently discovered a supposedly long non-coding RNA (lncRNA) transcript shifting from ribosomal subunits to the polysome fractions upon translational rewiring induced by ISR. It was shown that sometimes lncRNA’s can code for micropeptides which were previously overlooked due to its small size that makes them undetectable by routinely proteomics approaches. Strikingly, analysis of coding potential and in deep targeted proteomics of melanoma cells identified a micropeptide produced from this transcript. In the past period, an increasing number of these “lncRNAs” encoded micropeptides have been identified and a fraction of them seems to have a biological function. Additionally, an rRNA-specific methyltransferase was also found to be downregulated upon the translational switch. Importantly loss of this modification was associated in mice with decreased translation and defects in stem cell differentiation capacity, thus suggesting that the enzyme could be implicated in the translational rewiring and dedifferentiation process induced upon the development of therapy resistance. Overall this project aims at investigating the role of the rRNA-specific m6A methyltransferase in the translational rewiring including the translation of specific and otherwise 'non-coding' RNAs. Additionally, the possible function of the micropeptide for melanoma progression and therapy resistance will also be evaluated.