Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm(-/-)) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm(-/-) animals exhibit increased abundance of alpha smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA. Cancer-associated fibroblasts (CAFs) are a major component of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDA). Here the authors report the importance of macrophage-derived Oncostatin M in reprogramming CAFs to drive a pro-tumorigenic environment in PDA.

Automated summary

The study highlights the crucial role of macrophage-derived Oncostatin M in reprogramming cancer-associated fibroblasts to drive a pro-tumorigenic environment in pancreatic ductal adenocarcinoma.