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

Brian Y. Lee; Elizabeth Hogg; Christopher Below; Alexander Kononov; Adrian Blanco Gomez; Felix Heider; Jingshu Xu; Colin Hutton; Xiaohong Zhang; Tamara Scheidt; Kenneth Beattie; Angela Lamarca; Mairead Mcnamara; Juan Valle; Claus Jorgensen

doi:10.1038/s41467-021-27607-8

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

Brian Y. Lee, Elizabeth Hogg, Christopher Below, Alexander Kononov, Adrian Blanco Gomez, Felix Heider, Jingshu Xu, Colin Hutton, Xiaohong Zhang, Tamara Scheidt, Kenneth Beattie, Angela Lamarca, Mairead Mcnamara, Juan Valle, Claus Jorgensen

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

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
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27607-8
Publication status	Published - 17 Dec 2021

Keywords

Adenocarcinoma/metabolism
Animals
Cancer-Associated Fibroblasts/metabolism
Carcinoma, Pancreatic Ductal/metabolism
Cell Communication
Cell Line, Tumor
Cell Proliferation
Granulocyte-Macrophage Colony-Stimulating Factor/metabolism
Immunosuppression Therapy
Inflammation/metabolism
Macrophages/pathology
Male
Mice, Inbred C57BL
Neoplasm Metastasis
Oncostatin M/metabolism
Pancreatic Neoplasms/metabolism
Pancreatic Stellate Cells/metabolism
Receptors, Oncostatin M/metabolism
Signal Transduction
Tumor Microenvironment
Mice

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

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

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Lee, B. Y., Hogg, E., Below, C., Kononov, A., Blanco Gomez, A., Heider, F., Xu, J., Hutton, C., Zhang, X., Scheidt, T., Beattie, K., Lamarca, A., Mcnamara, M., Valle, J., & Jorgensen, C. (2021). Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis. Nature Communications, 12(1), Article 7336. https://doi.org/10.1038/s41467-021-27607-8

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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 = "Adenocarcinoma/metabolism, Animals, Cancer-Associated Fibroblasts/metabolism, Carcinoma, Pancreatic Ductal/metabolism, Cell Communication, Cell Line, Tumor, Cell Proliferation, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism, Immunosuppression Therapy, Inflammation/metabolism, Macrophages/pathology, Male, Mice, Inbred C57BL, Neoplasm Metastasis, Oncostatin M/metabolism, Pancreatic Neoplasms/metabolism, Pancreatic Stellate Cells/metabolism, Receptors, Oncostatin M/metabolism, Signal Transduction, Tumor Microenvironment, Mice",

author = "Lee, {Brian Y.} and Elizabeth Hogg and Christopher Below and Alexander Kononov and {Blanco Gomez}, Adrian and Felix Heider and Jingshu Xu and Colin Hutton and Xiaohong Zhang and Tamara Scheidt and Kenneth Beattie and Angela Lamarca and Mairead Mcnamara and Juan Valle and Claus Jorgensen",

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

year = "2021",

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

language = "English",

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Lee, BY, Hogg, E, Below, C, Kononov, A, Blanco Gomez, A, Heider, F, Xu, J, Hutton, C, Zhang, X, Scheidt, T, Beattie, K, Lamarca, A, Mcnamara, M , Valle, J & Jorgensen, C 2021, 'Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis', Nature Communications, vol. 12, no. 1, 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

AU - Below, Christopher

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, Mairead

AU - Valle, Juan

AU - Jorgensen, Claus

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 - Adenocarcinoma/metabolism

KW - Animals

KW - Cancer-Associated Fibroblasts/metabolism

KW - Carcinoma, Pancreatic Ductal/metabolism

KW - Cell Communication

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Granulocyte-Macrophage Colony-Stimulating Factor/metabolism

KW - Immunosuppression Therapy

KW - Inflammation/metabolism

KW - Macrophages/pathology

KW - Male

KW - Mice, Inbred C57BL

KW - Neoplasm Metastasis

KW - Oncostatin M/metabolism

KW - Pancreatic Neoplasms/metabolism

KW - Pancreatic Stellate Cells/metabolism

KW - Receptors, Oncostatin M/metabolism

KW - Signal Transduction

KW - Tumor Microenvironment

KW - Mice

U2 - 10.1038/s41467-021-27607-8

DO - 10.1038/s41467-021-27607-8

M3 - Article

C2 - 34921158

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7336

ER -

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

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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