TY - JOUR
T1 - Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis
AU - Lee, Brian Y.
AU - Hogg, Elizabeth K. J.
AU - Below, Christopher R.
AU - Kononov, Alexander
AU - Blanco-Gomez, Adrian
AU - Heider, Felix
AU - Xu, Jingshu
AU - Hutton, Colin
AU - Zhang, Xiaohong
AU - Scheidt, Tamara
AU - Beattie, Kenneth
AU - Lamarca, Angela
AU - McNamara, Mairéad
AU - Valle, Juan W.
AU - Jørgensen, Claus
N1 - Funding Information:
This work was supported by Cancer Research UK Institute Awards A19258, Experimental Medicine Programme Award (A25236) and European Research Council Consolidator Award (ERC-2017-COG 772577). Dr. Angela Lamarca was part-funded by The Christie Charity. The authors would like to acknowledge colleagues at CRUK Manchester Institute Systems Oncology Team, CRUK Manchester Institute core facilities: Flow Cytometry, Molecular Biology Core Facility and Visualisation, Irradiation and Analysis, the Biological Research Unit and Transgenic Breeding Facility. The authors would also like to acknowledge Dr. Dieter Saur, Dr. Ronald DePinho, Dr. Kris Freese, Dr. Raul Urrutia, Dr. Didier Trono and Dr. Tim Somervaille for kindly sharing cell lines and plasmids and Dr. Santiago Zelenay for fruitful discussion and help with figures. Figure panels 5a and 7e were generated with help from Biorender (www.biorender.com). The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/17
Y1 - 2021/12/17
N2 - 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.
AB - 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.
KW - Cancer microenvironment
KW - Cell signalling
KW - Tumour immunology
UR - http://www.scopus.com/inward/record.url?scp=85121568878&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27607-8
DO - 10.1038/s41467-021-27607-8
M3 - Article
C2 - 34921158
AN - SCOPUS:85121568878
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
M1 - 7336
ER -
