RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming

Huilong Yin, Xiang Zhang, Pengyuan Yang, Xiaofang Zhang, Yingran Peng, Da Li, Yanping Yu, Ye Wu, Yidi Wang, Jinbao Zhang, Xiaochen Ding, Xiangpeng Wang, Angang Yang () and Rui Zhang ()
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Huilong Yin: Fourth Military Medical University
Xiang Zhang: Fourth Military Medical University
Pengyuan Yang: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Xiaofang Zhang: Fourth Military Medical University
Yingran Peng: Fourth Military Medical University
Da Li: Fourth Military Medical University
Yanping Yu: The Second Ward of Gynecological Tumor, Shaanxi Provincial Tumor Hospital
Ye Wu: Fourth Military Medical University
Yidi Wang: Fourth Military Medical University
Jinbao Zhang: Fourth Military Medical University
Xiaochen Ding: Fourth Military Medical University
Xiangpeng Wang: Xinxiang Medical University
Angang Yang: Fourth Military Medical University
Rui Zhang: Fourth Military Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21514-8

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