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High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1
Author(s) -
Steins Anne,
van Mackelenbergh Madelaine G,
van der Zalm Amber P,
Klaassen Remy,
Serrels Bryan,
Goris Sandrine G,
Kocher Hemant M,
Waasdorp Cynthia,
de Jong Joan H,
Tekin Cansu,
Besselink Marc G,
Busch Olivier R,
van de Vijver Marc J,
Verheij Joanne,
Dijk Frederike,
van Tienhoven Geertjan,
Wilmink Johanna W,
Medema Jan Paul,
van Laarhoven Hanneke WM,
Bijlsma Maarten F
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948780
Subject(s) - stroma , mesenchymal stem cell , stromal cell , cancer research , tumor microenvironment , hepatic stellate cell , biology , epithelial–mesenchymal transition , chemistry , pathology , downregulation and upregulation , microbiology and biotechnology , medicine , immunohistochemistry , immunology , tumor cells , endocrinology , biochemistry , gene
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.