Research Paper Volume 15, Issue 20 pp 10897—10914
WNT enhancing signals in pancreatic cancer are transmitted by LGR6
- 1 Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Ludwig-Maximilians-University (LMU), Munich, Bavaria, Germany
- 2 Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, P.R. China
- 3 Department of Surgery, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Bavaria, Germany
- 4 German Cancer Consortium (DKTK), Partner Site Munich, Munich, Bavaria, Germany
- 5 Bavarian Cancer Research Center (BZKF), LMU Munich, Munich, Bavaria, Germany
Received: April 3, 2023 Accepted: July 17, 2023 Published: September 27, 2023
https://doi.org/10.18632/aging.205101How to Cite
Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The G-protein-coupled receptor LGR6 associates with ligands of the R-Spondin (RSPO) family to potentiate preexisting signals of the canonical WNT pathway. However, its importance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we show that LGR6 is differentially expressed in various PDAC cell lines of mesenchymal and epithelial phenotype, respectively, siding with the latter subsets. LGR6 expression is altered based upon the cells’ WNT activation status. Furthermore, extrinsic enhancement of WNT pathway signaling increased LGR6 expression suggestive of a reinforcing self-regulatory loop in highly WNT susceptible cells. Downregulation of LGR6 on the other hand, seemed to tamper those effects. Last, downregulation of LGR6 reduced cancer stemness as determined by functional in vitro assays. These findings shed new insights into regulatory mechanisms for the canonical WNT pathway in pancreatic cancer cells. It may also have potential value for treatment stratification of PDAC.
Abbreviations
DFS: Disease-free survival; OS: Overall survival; PDAC: Pancreatic ductal adenocarcinoma; RSPO: R-Spondin; PKA: Protein kinase A; TCF/LEF binding sites: T-cell factor/lymphoid enhancer factor; LGR4/5/6: Leucine-rich repeat containing G-protein coupled receptors 4/5/6; EMT: Epithelial–mesenchymal transition; GSEA: Gene set enrichment analysis; MsigDB: Molecular Signature Database; ES: Enrichment scores; SFA: sphere-formation assay; CSCs: Cancer stem cells; WB: Western blot.