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

• Published in: Nature communications Vol. 14; no. 1; pp. 6885 - 18
• Main Authors: Shu, Zhaoqi, Fan, Minghe, Tu, Bo, Tang, Zhiheng, Wang, Haojie, Li, Haimeng, Li, Hengchao, Yuan, Meng, Bai, Jingru, Huo, Sihan, Wang, Lina, Zhu, Wei-Guo, Wang, Wei, Liu, Xiaoyun, Shu, Shaokun, Zhao, Ying
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 13/21; 13/51; 38/15; 38/39; 38/70; 38/91; 45/77; 631/67/1504/1713; 631/80/86/2368; 692/4028/67/327; 82/80; 96/95; Adenocarcinoma; Animals; Cancer; Cancer-Associated Fibroblasts - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Line, Tumor; Epithelial cells; Epithelium; Epithelium - metabolism; Fibroblasts; Fibroblasts - metabolism; Humanities and Social Sciences; Mice; multidisciplinary; Pancreas; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Proprotein Convertase 9 - metabolism; Science; Science (multidisciplinary); Signal transduction; Stroma; Tumor cells; Tumor Microenvironment; Tumors; Weight reduction; Wnt protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42508-8

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. Crosstalk between tumor cells and the microenvironment is essential for tumor progression. Here, the authors show Pancreatic ductal adenocarcinoma (PDAC) epithelial cells with high level of Lin28b secrete Wnt5a to upregulate Lin28b expression in cancer-associated fibroblasts, which in turn promote growth of PDAC cells via production of PCSK9.