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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.

SUBMITTER: Lee BY

PROVIDER: S-EPMC8683436 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Lee Brian Y BY Hogg Elizabeth K J EKJ Below Christopher R CR Kononov Alexander A Blanco-Gomez Adrian A Heider Felix F Xu Jingshu J Hutton Colin C Zhang Xiaohong X Scheidt Tamara T Beattie Kenneth K Lamarca Angela A McNamara Mairéad M Valle Juan W JW Jørgensen Claus C

Nature communications 20211217 1

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 ex ...[more]

PMID: 34921158

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive nature and dismal prognosis, largely attributed to its unique tumor microenvironment. However, the molecular mechanisms by which tumor-associated macrophages (TAMs) promote PDAC progression, particularly the role of β-catenin signaling in regulating TAM phenotype and function, remain incompletely understood. Initially, we performed comprehensive analyses of RNA-seq and single-cell RNA-seq (scRNA-seq) datasets to investigate OSM and LOXL2 expression patterns in PDAC. Subsequently, the regulatory relationship between β-catenin and OSM in TAMs was examined using THP-1-derived macrophages. Furthermore, the functional impact of TAM-derived OSM on PDAC progression was evaluated through in vitro co-culture systems and an in vivo Panc02 lung metastasis model. Additionally, mechanistic studies employed pharmacological inhibitors and genetic approaches targeting β-catenin, OSM, and STAT3 signaling. Notably, elevated expression of OSM and LOXL2 in PDAC specimens significantly correlated with poor patient survival. Intriguingly, scRNA-seq analysis revealed that β-catenin signaling was uniquely activated in TAMs among immune cells, which consequently regulated both TAM polarization and OSM expression. These OSM-expressing TAMs exhibited a distinct hybrid M1/M2 phenotype. Besides, our transcriptional profiling of TAMs revealed concurrent activation of both pro- and anti-inflammatory programs, with enrichment in Wnt signaling pathways. RNA-seq analysis of PDAC cells exposed to TAM-derived factors demonstrated enhanced mesenchymal transition and stemness properties, with direct enrichment of OSM signaling and extracellular matrix remodeling pathways. Mechanistically, β-catenin activation directly regulated both TAM phenotype and OSM expression, while TAM-conditioned medium enhanced PDAC cell migration, invasion, and lung metastasis. Importantly, inhibition of β-catenin signaling simultaneously altered TAM polarization and reduced OSM expression, which substantially attenuated epithelial-mesenchymal transition (EMT) in co-cultured PDAC cells. Moreover, STAT3 inhibition abolished OSM-induced LOXL2 expression and subsequent EMT programming. Collectively, we identified a novel β-catenin/OSM-STAT3/LOXL2 signaling axis mediating TAM-induced PDAC progression. This pathway not only elucidates a previously unrecognized mechanism of β-catenin-mediated regulation of TAM function and phenotype but also presents potential therapeutic targets for intervention.

Dataset Information

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

Publications

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

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