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 (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.

Research trends in pharmacological modulation of tumor‐associated macrophages

“…Upon binding to its ligands including CSF‐1 or IL‐34, CSF‐1R undergoes dimerization and therefore causes a signaling cascade that facilitates the proliferation, functioning, and survival of macrophages. High expression of CSF‐1 has been found in breast, prostate, pancreatic, gastric, and many other types of cancers, and its level has been closely associated with TAMs density and poor prognosis 120–123 . It is found that CSF‐1‐positive cancer cells colocalize with abundant CSF‐1R‐positive TAMs in invasive breast cancer, and the CSF‐1/CSF‐1R axis is significantly correlated with a higher grade, basal‐like phenotype, and lymph node metastasis 124 .…”

An Immunological Glance on Pancreatic Ductal Adenocarcinoma

“…The overall survival of PDAC patients highly depends on the type of stroma and potentially also on the stromal plasticity. Steins and colleagues demonstrated that cancer cells with epithelial phenotype could activate PSCs and thus lead to the deposition of collagen [39]. In contrast, mesenchymal cancer cells featuring elevated secretion of CSF-1 show opposite effects [39], indicating that stromal composition and its plasticity may be reflected by the differentiation grade of cancer cells.…”

Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets

“…However, stromal depletion strategies had disappointing clinical results, suggesting that PDAC stroma also harbors tumor-restraining properties that suggest that a complex stromal plasticity exists (7)(8)(9).…”