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dc.contributor.authorNeuzillet, Cen_US
dc.contributor.authorTijeras-Raballand, Aen_US
dc.contributor.authorRagulan, Cen_US
dc.contributor.authorCros, Jen_US
dc.contributor.authorPatil, Yen_US
dc.contributor.authorMartinet, Men_US
dc.contributor.authorErkan, Men_US
dc.contributor.authorKleeff, Jen_US
dc.contributor.authorWilson, Jen_US
dc.contributor.authorApte, Men_US
dc.contributor.authorTosolini, Men_US
dc.contributor.authorWilson, ASen_US
dc.contributor.authorDelvecchio, FRen_US
dc.contributor.authorBousquet, Cen_US
dc.contributor.authorParadis, Ven_US
dc.contributor.authorHammel, Pen_US
dc.contributor.authorSadanandam, Aen_US
dc.contributor.authorKocher, HMen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2019-02-20T07:45:37Z
dc.date.issued2019-05en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/30575030en_US
dc.identifier.citationJ Pathol, 2019, 248 (1), pp. 51 - 65en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3059
dc.identifier.eissn1096-9896en_US
dc.identifier.doi10.1002/path.5224en_US
dc.description.abstractCancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- versus anti-tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient-derived CAF primary cultures, we demonstrated that human PDAC-derived CAFs display a high level of inter- and intra-tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC-derived CAFs (pCAFassigner). Multiple CAF subtypes co-existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix- and immune-related signatures, vimentin and α-smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non-tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF-like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter- and intra-tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single-cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.en_US
dc.format.extent51 - 65en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectpancreatic stellate cellen_US
dc.subjectstromaen_US
dc.subjecttranscriptomicsen_US
dc.subjecttumour microenvironmenten_US
dc.subjecttumour-stroma interactionsen_US
dc.titleInter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-12-18en_US
rioxxterms.versionofrecord10.1002/path.5224en_US
rioxxterms.licenseref.startdate2019-05en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfJ Patholen_US
pubs.issue1en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Systems and Precision Cancer Medicine
pubs.publication-statusPublisheden_US
pubs.volume248en_US
pubs.embargo.termsNot knownen_US
icr.researchteamSystems and Precision Cancer Medicineen_US
dc.contributor.icrauthorSadanandam, Angurajen_US


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