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

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    Authors
    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.
    Beattie, K.
    Lamarca, Angela
    McNamara, Mairéad G
    Valle, Juan W
    Jørgensen, Claus
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    Affiliation
    Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, SK10 4TG Manchester, UK
    Issue Date
    2021
    
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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.
    Citation
    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.
    Journal
    Nature Communications
    URI
    http://hdl.handle.net/10541/625000
    DOI
    10.1038/s41467-021-27607-8
    PubMed ID
    34921158
    Additional Links
    https://dx.doi.org/10.1038/s41467-021-27607-8
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41467-021-27607-8
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