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

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 and Claus Jørgensen ()
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Brian Y. Lee: The University of Manchester
Elizabeth K. J. Hogg: The University of Manchester
Christopher R. Below: The University of Manchester
Alexander Kononov: The University of Manchester
Adrian Blanco-Gomez: The University of Manchester
Felix Heider: The University of Manchester
Jingshu Xu: The University of Manchester
Colin Hutton: The University of Manchester
Xiaohong Zhang: The University of Manchester
Tamara Scheidt: University of Salzburg
Kenneth Beattie: University of Dundee
Angela Lamarca: The Christie NHS Foundation Trust
Mairéad McNamara: The Christie NHS Foundation Trust
Juan W. Valle: The Christie NHS Foundation Trust
Claus Jørgensen: The University of Manchester

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27607-8

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