Increased Gremlin1 Expression in Pancreatic Ductal Adenocarcinoma Promotes a Fibrogenic Stromal Microenvironment.

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) microenvironment is primarily composed of cancer-associated fibroblasts and immune cells. Gremlin1 (Grem1) is a profibrogenic factor that promotes tumorigenesis in several cancers. However, the role of Grem1 in the PDAC microenvironment is not defined.

Materials and methods: We correlated Grem1 levels with activated stroma and immune cells in human PDAC using The Cancer Genome Atlas RNA-sequencing data and characterized expression of Grem1 transcripts and isoforms in pancreatic cell lines and PDAC tissues. We assessed the role of Grem1 in the microenvironment by in vitro studies.

Results: Grem1 expression is associated with an activated stroma and increased M1 and M2 macrophages. Only full length Grem1 variant 1 and isoform 1 were detectable in human pancreatic cells, and remarkably high levels of Grem1 were observed in pancreatic fibroblasts. Immunohistochemistry detected Grem1 protein in PDAC tumor and stromal cells, which correlated with infiltrating macrophages in PDAC tumors. Grem1 knockdown in cancer-associated fibroblasts suppressed transforming growth factor β-induced extracellular matrix proteins. Grem1 recombinant protein treatment in vitro increased M1 and M2 macrophages.

Conclusions: Grem1 acts as a profibrogenic factor in the PDAC microenvironment via modulation of fibroblasts and macrophages. Grem1 may have the potential to be developed as a therapeutic target for PDAC.