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Title:
RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming | Nature Communications
Description:
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. N6-methyladenosine (m6A) is a reversible mRNA modification with important roles in cancer biology and immunoregulation. Here, the authors show that myeloid-specific deletion of Mettl3, the catalytic subunit of the methyltransferase complex, promotes tumor growth and metastasis in preclinical tumor models, influencing macrophage reprogramming and attenuating PD-1 blockade.
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headline:RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming
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description: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. N6-methyladenosine (m6A) is a reversible mRNA modification with important roles in cancer biology and immunoregulation. Here, the authors show that myeloid-specific deletion of Mettl3, the catalytic subunit of the methyltransferase complex, promotes tumor growth and metastasis in preclinical tumor models, influencing macrophage reprogramming and attenuating PD-1 blockade.
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address:
name:The Second Ward of Gynecological Tumor, Shaanxi Provincial Tumor Hospital, Xiâan, China
type:PostalAddress
type:Organization
name:Ye Wu
affiliation:
name:Fourth Military Medical University
address:
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Yidi Wang
affiliation:
name:Fourth Military Medical University
address:
name:Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Jinbao Zhang
affiliation:
name:Fourth Military Medical University
address:
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Xiaochen Ding
affiliation:
name:Fourth Military Medical University
address:
name:Department of Experimental Surgery, Xijing Hospital, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Xiangpeng Wang
affiliation:
name:Xinxiang Medical University
address:
name:Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
type:PostalAddress
type:Organization
name:Xinxiang Medical University
address:
name:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
type:PostalAddress
type:Organization
name:Angang Yang
url:http://orcid.org/0000-0002-8854-4672
affiliation:
name:Fourth Military Medical University
address:
name:The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Xinxiang Medical University
address:
name:Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
type:PostalAddress
type:Organization
name:Xinxiang Medical University
address:
name:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
type:PostalAddress
type:Organization
email:[email protected]
name:Rui Zhang
url:http://orcid.org/0000-0002-6147-1573
affiliation:
name:Fourth Military Medical University
address:
name:The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
name:Fourth Military Medical University
address:
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xiâan, China
name:Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:The Second Ward of Gynecological Tumor, Shaanxi Provincial Tumor Hospital, Xiâan, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xiâan, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
name:Department of Experimental Surgery, Xijing Hospital, Fourth Military Medical University, Xiâan, China
name:Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xiâan, China
name:Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
name:The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xiâan, China
name:The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xiâan, China
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