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METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity

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Abstract

Purpose

Although immunotherapy improves clinical outcomes in several types of malignancies, as an immunologically ‘cold’ tumor, pancreatic ductal adenocarcinoma (PDAC) is arrantly resistant to immunotherapy. However, the role of N6-methyladenosine (m6A) modification in the immune microenvironment of PDAC is still poorly understood.

Methods

The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to identify differentially expressed m6A related enzymes. The biological role and mechanism of METTL3 in PDAC growth and metastasis were determined in vitro and in vivo. RNA-sequencing and bioinformatics analysis were used to identify signaling pathways involved in METTL3. Western blot, m6A dot blot assays, co-immunoprecipitation, immunofluorescence, and flow cytometry were used to explore the molecular mechanism.

Results

Here, we demonstrate that METTL3, the key regulator of m6A modification, is downregulated in PDAC, and negatively correlates with PDAC malignant features. Elevated METTL3 suppresses PDAC growth and overcomes resistance to immune checkpoint blockade. Mechanistically, METTL3 promotes the accumulation of endogenous double-stranded RNA (dsRNA) through protecting m6A-transcripts from further Adenosine-to-inosine (A-to-I) editing. The dsRNA stress activates RIG-I-like receptors (RLRs) to enhance anti-tumor immunity, finally suppressing PDAC progression.

Conclusion

Our findings indicate that tumor cell-intrinsic m6A modification participates in the regulation of tumor immune landscape. Adjusting the m6A level may be an effective strategy to overcome the resistance to immunotherapy and increase responsiveness to immunotherapy in PDAC.

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Data availability

Full data will be available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Prof. Jing Xue for the gift of KPC mice derived PDAC cell line FC1199.

Funding

The research was supported by grants from the National Postdoctoral Program for Innovative Talents, Initiative Postdocs Supporting Program (BX2021187), Shanghai Pstdoctoral Excellence Program (2021499), China Postdoctoral Science Foundation (2021M702161), the National Natural Science Foundation of China (81902370), and the Natural Science Foundation of Shanghai (22ZR1460000, 21ZR1461300).

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Author notes

  1. Lili Zhu, Botai Li and Rongkun Li contributed equally.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Immune Therapy Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Lili Zhu & Botai Li

  2. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Lili Zhu, Lipeng Hu, Yanli Zhang, Zhigang Zhang, Shuheng Jiang & Xueli Zhang

  3. Institute of Oncology, Affiliated Hospital of Jiangsu University, Zhenjiang, China

    Rongkun Li

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  1. Lili Zhu
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Contributions

Lili Zhu, Botai Li and Rongkun Li designed and performed experiments, analyzed data and wrote the manuscript; Yanli Zhang and Lipeng Hu performed experiments and analyzed the data, Zhigang Zhang, Shuheng Jiang and Xueli Zhang edited the manuscript; Shuheng Jiang and Xueli Zhang supervised the study, obtained funding and provided critical review. All authors approved the final version of the manuscript.

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Correspondence to Shuheng Jiang or Xueli Zhang.

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Animal experiments were performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals and relevant Chinese laws and regulations. The protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Shanghai Jiao Tong University, the Animal Protocol number is A2020108. Ethical approval was obtained from the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University.

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Zhu, L., Li, B., Li, R. et al. METTL3 suppresses pancreatic ductal adenocarcinoma progression through activating endogenous dsRNA-induced anti-tumor immunity. Cell Oncol. 46, 1529–1541 (2023). https://doi.org/10.1007/s13402-023-00829-2

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