The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma

Menée à l'aide de lignées cellulaires, de modèles murins de métastases pulmonaires et d'échantillons tumoraux issus de patients atteints d'un adénocarcinome pulmonaire, cette étude examine la méthylation des ARN des cellules pulmonaires cancéreuses et met en évidence un mécanisme par lequel la méthylation m6A de l'ARN de la protéine EML4 favorise le processus métastatique

Résumé en anglais

Comprehensive m6A epitranscriptome profiling of primary tumors remains largely uncharted. Here, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating the corresponding transcriptome, proteome and extensive clinical annotations. We identified distinct clusters and genes that were exclusively linked to disease progression through m6A modifications. In comparison with NL tissues, we identified 430 transcripts to be hypo-methylated and 222 to be hyper-methylated in tumors. Among these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted the translation of EML4, leading to its widespread overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics through interacting with ARPC1A, enhancing lamellipodia formation, cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo.