RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

Menée in vitro et à l'aide de modèles murins de métastases pulmonaires, cette étude met en évidence un mécanisme par lequel la méthylation m6A de l'ARN messager des macrophages, en modifiant le programme traductionnel de ces derniers, favorise la croissance tumorale et le processus métastatique

Résumé en anglais

N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.