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The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium

Author

Listed:
  • Zhaoqi Shu

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Minghe Fan

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Bo Tu

    (the University of Texas MD Anderson Cancer Center
    Fred Hutchinson Cancer Research Center)

  • Zhiheng Tang

    (Peking University Health Science Center)

  • Haojie Wang

    (Peking University Health Science Center and Peking University Cancer Hospital and Institute)

  • Haimeng Li

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Hengchao Li

    (FuDan University)

  • Meng Yuan

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Jingru Bai

    (Shenzhen University School of Medicine
    Shenzhen University)

  • Sihan Huo

    (Peking University Health Science Center
    Peking University Health Science Center)

  • Lina Wang

    (Peking University Health Science Center)

  • Wei-Guo Zhu

    (Shenzhen University School of Medicine
    Shenzhen University)

  • Wei Wang

    (Peking University, NHC Key Laboratory of Medical Immunology)

  • Xiaoyun Liu

    (Peking University Health Science Center)

  • Shaokun Shu

    (Peking University Health Science Center)

  • Ying Zhao

    (Peking University Health Science Center
    Peking University Health Science Center)

Abstract

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9’s production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in bidirectional crosstalk between pancreatic tumor epithelium and TME and results in a pro-‍tumorigenic contexture.

Suggested Citation

  • Zhaoqi Shu & Minghe Fan & Bo Tu & Zhiheng Tang & Haojie Wang & Haimeng Li & Hengchao Li & Meng Yuan & Jingru Bai & Sihan Huo & Lina Wang & Wei-Guo Zhu & Wei Wang & Xiaoyun Liu & Shaokun Shu & Ying Zha, 2023. "The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42508-8
    DOI: 10.1038/s41467-023-42508-8
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    References listed on IDEAS

    as
    1. Xinjian Liu & Xuhui Bao & Mengjie Hu & Hanman Chang & Meng Jiao & Jin Cheng & Liyi Xie & Qian Huang & Fang Li & Chuan-Yuan Li, 2020. "Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer," Nature, Nature, vol. 588(7839), pages 693-698, December.
    2. Akshay T. Krishnamurty & Justin A. Shyer & Minh Thai & Vineela Gandham & Matthew B. Buechler & Yeqing Angela Yang & Rachana N. Pradhan & Amber W. Wang & Patricia L. Sanchez & Yan Qu & Beatrice Breart , 2022. "LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity," Nature, Nature, vol. 611(7934), pages 148-154, November.
    3. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
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