Novel bioinformatics mRNA translation multi-omics analysis identifies key features of the intestinal cancer stem cells

Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and cause relapses. CSCs high plasticity is essential for cancer adaptation through phenotypic and functional cellular switch. In the intestine oncogenic driving mutations in the crypt stem cells (SC) drive neoplasia in mouse and human models. Even though the signaling pathways promoting intestinal CSC establishment have been largely described, there is still a lack of understanding of the key cellular actors that are necessary to execute them. tRNAs are heterogeneous and highly modified molecules necessary to correctly translate mRNAs into proteins. Interestingly, a growing amount of data suggests that differential expression of tRNA pools plays a key role in defining cellular fate. Here, we aim to identify key features of intestinal CSC from the innovative perspective of tRNA heterogeneity and codon-dependent regulation of translation. To this end, we translationally profiled pure murine SC and CSC populations and generate a novel predictive bioinformatics analysis pipeline to uncover a set of CSC translational actors that specifically characterize their translational landscape. Interestingly, we identify a signature of tRNAs, tRNA modifying enzymes and associated mRNA codons that specifically cluster intestinal CSC from SC, bulk healthy intestinal cells and cancer intestinal tissue. Importantly, our CSC translational signature better predict intestinal CSC identity compared to canonical transcriptional signatures such as the Wnt-associated genes. Our findings suggest that codon-biased translational regulation is a novel layer of intestinal CSC characterization opening new prospective for cancer treatment and early diagnostics