The N6-methyladenosine Epitranscriptomic Landscape of Lung Adenocarcinoma [RNA-seq]

N6-methyladenosine (m6A) modification plays a central role in both RNA and tumor biology. Yet comprehensive m6A epitranscriptome profiling of primary tumors remains uncharted. To fill this gap, we profiled the m6A epitranscriptome of 10 non-neoplastic lung (NL) tissues and 51 lung adenocarcinoma (LUAD) tumors, integrating them with corresponding transcriptome, proteome and extensive clinical annotation. A total of 8,030 genes are marked with m6A modification, with variable abundances across tumors. Distinct clusters and genes were found to be linked exclusively to disease progression through m6A, rather than mRNA or protein levels. In comparison with NL tissues, 430 transcripts were hypo-methylated in tumors, and 222 were hyper-methylated. Fully 69% of these had no influence on RNA abundances. Amongst these genes, EML4 emerged as a novel metastatic driver, displaying significant hyper-methylation in tumors. m6A modification promoted EML4 translation and led to widespread EML4 overexpression in primary tumors. Functionally, EML4 modulated cytoskeleton dynamics and cell morphology, triggering cellular protrusions and enhancing cellular motility, local invasion, and metastasis. Clinically, high EML4 protein abundance correlated with features of metastasis. A METTL3 small molecule inhibitor markedly diminished both EML4 m6A and protein abundance, and efficiently suppressed lung metastases in vivo. Our findings unveil a dynamic and functional epitranscriptomic landscape in lung adenocarcinoma, pinpointing the hyper-methylation of EML4 as a key driver of tumor metastasis.