High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1
Open Access
- 16 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in EMBO Reports
- Vol. 21 (5), e48780
- https://doi.org/10.15252/embr.201948780
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high‐grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component of stroma, the pancreatic stellate cells (PSCs). We found in primary tissue that high‐grade PDAC had reduced collagen deposition compared to low‐grade PDAC. Xenografts and organotypic co‐cultures established from mesenchymal‐like PDAC cells featured reduced collagen and activated PSC content. Medium transfer experiments using a large set of PDAC cell lines revealed that mesenchymal‐like PDAC cells consistently downregulated ACTA2 and COL1A1 expression in PSCs and reduced proliferation. We identified colony‐stimulating factor 1 as the mesenchymal PDAC‐derived ligand that deactivates PSCs, and inhibition of its receptor CSF1R was able to counteract this effect. In conclusion, high‐grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF1R offers direct options to maintain a tumor‐restricting microenvironment.Keywords
Funding Information
- KWF Kankerbestrijding (UVA 2013‐5932, UVA 2012‐5607)
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