Abstract
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 α 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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment
Differential gene expression analysis of inflammatory CAFs (iCAFs) and myofibroblastic CAFs (myCAF) subsets[29] identified several membrane receptors, such as Osmr, Antxr[1] and Il1r1, which were expressed at a higher level in iCAFs (Fig. 1a)
Single-cell RNA-sequencing confirmed expression of Osmr, Antxr[1] and Il1r1 in cancer-associated fibroblasts (CAFs) as well as in endothelial and perivascular cells in both human and murine PDA27,33. These receptors were expressed at higher levels in iCAFs compared to myCAFs and antigen-presenting CAFs (apCAFs) (Fig. 1b, c and Supplementary Fig. 1a, b)
Summary
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. 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. The tumour microenvironment of Osm−/− animals exhibit increased abundance of α 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. Dysregulated immune cells and cancer-associated fibroblasts (CAFs) are a perpetual and dynamically regulated feature throughout PDA development[2,4]. The mechanisms by which discrete stromal populations coordinate to regulate specific tumour functions remain incompletely characterised[2,22]
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