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Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis
Lee, B. Y. Hogg, E. K. J. Below, C. R. Kononov, A. Blanco-Gomez, A. Heider, F. Xu, J. Hutton, C. Zhang, X. Scheidt, T.
Lee, B. Y.
Hogg, E. K. J.
Below, C. R.
Kononov, A.
Blanco-Gomez, A.
Heider, F.
Xu, J.
Hutton, C.
Zhang, X.
Scheidt, T.
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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.
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Date
2021
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Article
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Lee BY, Hogg EKJ, Below CR, Kononov A, Blanco-Gomez A, Heider F, et al. Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nature Communications. 2021;12(1):20.