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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 |

REPOSITORIES: biostudies-literature

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Heterocellular OSM-OSMR signalling drives pancreatic cancer growth and metastasis through functional fibroblast reprogramming

Project description:Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterised by a pathological fibroinflammatory microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remains incompletely characterised. Here, we describe how heterocellular OSM-OSMR signalling instructs fibroblast reprogramming, tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumorigenic 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 did not metastasise. Moreover, the tumour microenvironment of Osm-/- animals exhibit increased abundance of αSMApos 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-tumorigenic environment in PDA.

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Heterocellular OSM-OSMR signalling drives pancreatic tumour growth and metastasis through functional fibroblast reprogramming

Project description:Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy characterised by a pathologicalfibroinflammatorymicroenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however thedisparate effect of individual stromal subsets remains incompletely characterised. Here, we describe how heterocellular OSM-OSMR signalling instructsfibroblast reprogramming,tumourgrowth and metastasis.Macrophage-secreted OSM stimulatesinflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumorigenic environment and engage tumour cellsurvival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm-/-) mice display an epithelial-dominated morphology, reduced tumour growth and did notmetastasise. Moreover, the tumour microenvironment of Osm-/-animals exhibit increased abundance of αSMAposmyofibroblasts 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-tumorigenic environment in PDA.

2021-11-29 | PXD022484 | Pride

Heterocellular OSM-OSMR signalling drives pancreatic cancer growth and metastasis through functional fibroblast reprogramming

Project description:Heterocellular OSM-OSMR signalling drives pancreatic cancer growth and metastasis through functional fibroblast reprogramming

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Metastasis-associated fibroblasts promote angiogenesis in metastasized pancreatic cancer via the CXCL8 and the CCL2 axes.

Project description:The characteristic desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a key contributor to its lethality. This stromal microenvironment is populated by cancer-associated fibroblasts (CAFs) that interact with cancer cells to drive progression and chemo-resistance. Research has focused on CAFs in the primary tumour but not in metastases, calling into question the role of analogous metastasis-associated fibroblasts (MAFs). We infer a role of MAFs in murine hepatic metastases following untargeted treatment with the anti-angiogenic drug sunitinib in vivo. Treated metastases were smaller and had fewer stromal cells, but were able to maintain angiogenesis and metastasis formation in the liver. Furthermore, sunitinib was ineffective at reducing MAFs alongside other stromal cells. We speculate that cancer cells interact with MAFs to maintain angiogenesis and tumour progression. Thus, we tested interactions between metastatic pancreatic cancer cells and fibroblasts using in vitro co-culture systems. Co-cultures enhanced fibroblast proliferation and induced angiogenesis. We identify carcinoma-educated fibroblasts as the source of angiogenesis via secretions of CXCL8 (aka IL-8) and CCL2 (aka MCP-1). Overall, we demonstrate that metastasis-associated fibroblasts have potential as a therapeutic target and highlight the CXCL8 and CCL2 axes for further investigation.

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Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.

Project description:Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumours and metastases, and HOTAIR expression level in primary tumours is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb repressive complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings indicate that lincRNAs have active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.

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Molecular Simulation of Oncostatin M and Receptor (OSM-OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease.

Project description:Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM-OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM-OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM-OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the "hot spots" through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified "hotspots") mutant. Moreover, six cavities were detected at the OSM-OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM-OSMR complex and the identified "hot spots" constituting the core of the binding interface provide helpful information in understanding the OSM-OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

| S-EPMC7064634 | biostudies-literature

Gene-expression analysis of Oncostatin-M (OSM) signalling in cervical squamous cell carcinomas over-expressing the Oncostatin-M receptor (OSMR)

Project description:The type II Oncostatin M receptor (OSMR) serves as the main binding site for the pleiotropic cytokine OSM. We have previously demonstrated a positive correlation between copy number driven OSMR over-expression and adverse clinical outcome in cervical tumours and have also established enhanced angiogenic, migratory and invasive potential as major consequences of OSMR over-expression using cell-line models of cervical cancer. By analysis of gene expression patterns in cell lines and tumours, this study now systematically defines cohorts of genes that are implicated for the phenotypes observed. Importantly, we have identified 15 OSM induced genes that are involved in at least one of these key functions and are up-regulated in both OSMR over-expressing cell-lines and tumours. These genes can serve as markers of OSM signalling in OSMR over-expressing SCCs and represent suitable targets for functional characterisation. Gene expression of 4 cervical SCC cell lines analysed (2 with and 2 without OSMR overexpression) at 6 different time-points, with 3 replicates at each time-point.

2011-09-29 | E-GEOD-27480 | biostudies-arrayexpress

Gene-expression analysis of Oncostatin-M (OSM) signalling in cervical squamous cell carcinomas over-expressing the Oncostatin-M receptor (OSMR)

2011-09-30 | GSE27480 | GEO

Synaptic proximity enables NMDAR signalling to promote brain metastasis.

Project description:Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.

| S-EPMC6837873 | biostudies-literature

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