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; Claus Jørgensen

doi:10.1038/s41467-021-27607-8

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
, Claus Jørgensen (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

95 Citations (Scopus)

249 Downloads (Pure)

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.

Original language	English
Article number	7336
Number of pages	20
Journal	Nature Communications
Volume	12
DOIs	https://doi.org/10.1038/s41467-021-27607-8
Publication status	Published - 17 Dec 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cancer microenvironment
Cell signalling
Tumour immunology

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-021-27607-8Licence: CC BY

Final Published VersionFinal published version, 6.45 MBLicence: CC BY

Cite this

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, A., McNamara, M., Valle, J. W., & Jørgensen, C. (2021). Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nature Communications, 12, Article 7336. https://doi.org/10.1038/s41467-021-27607-8

@article{122de4cc89c04e308d2e4ac72be27ef3,

title = "Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis",

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.",

keywords = "Cancer microenvironment, Cell signalling, Tumour immunology",

author = "Lee, \{Brian Y.\} and Hogg, \{Elizabeth K. J.\} and Below, \{Christopher R.\} and Alexander Kononov and Adrian Blanco-Gomez and Felix Heider and Jingshu Xu and Colin Hutton and Xiaohong Zhang and Tamara Scheidt and Kenneth Beattie and Angela Lamarca and Mair{\'e}ad McNamara and Valle, \{Juan W.\} and Claus J{\o}rgensen",

note = "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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "17",

doi = "10.1038/s41467-021-27607-8",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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}

Lee, BY, Hogg, EKJ, Below, CR, Kononov, A, Blanco-Gomez, A, Heider, F, Xu, J, Hutton, C, Zhang, X, Scheidt, T, Beattie, K, Lamarca, A, McNamara, M, Valle, JW & Jørgensen, C 2021, 'Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis', Nature Communications, vol. 12, 7336. https://doi.org/10.1038/s41467-021-27607-8

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 - https://www.scopus.com/pages/publications/85121568878

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 -

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

Abstract

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