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

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.

• Authors: Brian Y Lee, Elizabeth K J Hogg, Christopher R Below, Alexander Kononov, Adrian Blanco-Gomez, Felix Heider, Jingshu Xu, Colin Hutton, Xiaohong Zhang, Tamara Scheidt, Kenneth Beattie, Angela Lamarca, Mairéad McNamara, Juan W Valle, Claus Jørgensen
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 7336 (12 17 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34921158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Receptors, Oncostatin M
• Oncostatin M
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Adenocarcinoma (metabolism, pathology)
• Animals
• Cancer-Associated Fibroblasts (metabolism, pathology)
• Carcinoma, Pancreatic Ductal (metabolism, pathology)
• Cell Communication
• Cell Line, Tumor
• Cell Proliferation
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Immunosuppression Therapy
• Inflammation (metabolism, pathology)
• Macrophages (pathology)
• Male
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Oncostatin M (metabolism)
• Pancreatic Neoplasms (metabolism, pathology)
• Pancreatic Stellate Cells (metabolism, pathology)
• Receptors, Oncostatin M (metabolism)
• Signal Transduction
• Tumor Microenvironment