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

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
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

UN SDGs

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

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

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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(1). 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 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",

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year = "2021",

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day = "17",

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

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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, no. 1. 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

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

ER -

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

Abstract

Keywords

UN SDGs

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