High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1

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 ( PSC s). 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 ACTA 2 and COL 1A1 expression in PSC s and reduced proliferation. We identified colony‐stimulating factor 1 as the mesenchymal PDAC ‐derived ligand that deactivates PSC s, and inhibition of its receptor CSF 1R was able to counteract this effect. In conclusion, high‐grade PDAC features stroma that is low in collagen and activated PSC content, and targeting CSF 1R offers direct options to maintain a tumor‐restricting microenvironment. image This study reveals that PDAC cells counteract mechanical restrictions of tumor stroma by secreting CSF ‐1, which could be a potential therapeutic target. Poorly differentiated, high‐grade pancreatic cancers, corresponding with the mesenchymal subtype, feature stroma that is low in collagen and activated pancreatic stellate cell content. These mesenchymal subtype cancer cells secrete high amounts of CSF ‐1. CSF ‐1 downregulates stromal activation markers and reduces proliferation via STAT 3 in PSC s. Depletion of CSF ‐1 in high‐grade PDAC abolishes PSC deactivation. High‐grade CSF ‐1‐positive PDAC patient samples exhibit deactivated stroma.