2. Academic Validation
  3. The Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium

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

  • Nat Commun. 2023 Oct 28;14(1):6885. doi: 10.1038/s41467-023-42508-8.
Zhaoqi Shu # 1 2,  Minghe Fan # 1 2,  Bo Tu # 3 4,  Zhiheng Tang 5,  Haojie Wang 6,  Haimeng Li 1 2,  Hengchao Li 7,  Meng Yuan 1 2,  Jingru Bai 8 9,  Sihan Huo 1 2,  Lina Wang 1,  Wei-Guo Zhu 8 9,  Wei Wang 10,  Xiaoyun Liu 5,  Shaokun Shu 2,  Ying Zhao 11 12
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China.
  • 2 Peking University International Cancer Institute, Peking University Health Science Center, Beijing, 100191, China.
  • 3 Molecular and Cellular Oncology Department, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
  • 5 Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 6 Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center and Peking University Cancer Hospital and Institute, Beijing, China.
  • 7 Department of Pancreatic Surgery, Huashan Hospital, Institute of Pancreatic Disease, FuDan University, Shanghai, 200040, China.
  • 8 Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, 518055, China.
  • 9 Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, China.
  • 10 Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology, Beijing, China.
  • 11 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. [email protected].
  • 12 Peking University International Cancer Institute, Peking University Health Science Center, Beijing, 100191, China. [email protected].
  • # Contributed equally.
PMID: 37898598 DOI: 10.1038/s41467-023-42508-8
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.

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