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

Author

Listed:
  • 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
    University of Manchester)

  • Mairéad McNamara

    (The Christie NHS Foundation Trust
    University of Manchester)

  • Juan W. Valle

    (The Christie NHS Foundation Trust
    University of Manchester)

  • Claus Jørgensen

    (The University of Manchester)

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.

Suggested Citation

  • 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 & An, 2021. "Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27607-8
    DOI: 10.1038/s41467-021-27607-8
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    Cited by:

    1. Yi Zhou & Panayiotis E. Stevis & Jing Cao & George Ehrlich & Jennifer Jones & Ashique Rafique & Mark W. Sleeman & William C. Olson & Matthew C. Franklin, 2024. "Structures of complete extracellular assemblies of type I and type II Oncostatin M receptor complexes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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