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

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 and Ying Zhao ()
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Zhaoqi Shu: Peking University Health Science Center
Minghe Fan: Peking University Health Science Center
Bo Tu: the University of Texas MD Anderson Cancer 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
Hengchao Li: FuDan University
Meng Yuan: Peking University Health Science Center
Jingru Bai: Shenzhen University School of Medicine
Sihan Huo: Peking University Health Science Center
Lina Wang: Peking University Health Science Center
Wei-Guo Zhu: Shenzhen University School of Medicine
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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42508-8

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