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dc.contributor.authorNeuzillet, C
dc.contributor.authorTijeras-Raballand, A
dc.contributor.authorRagulan, C
dc.contributor.authorCros, J
dc.contributor.authorPatil, Y
dc.contributor.authorMartinet, M
dc.contributor.authorErkan, M
dc.contributor.authorKleeff, J
dc.contributor.authorWilson, J
dc.contributor.authorApte, M
dc.contributor.authorTosolini, M
dc.contributor.authorWilson, AS
dc.contributor.authorDelvecchio, FR
dc.contributor.authorBousquet, C
dc.contributor.authorParadis, V
dc.contributor.authorHammel, P
dc.contributor.authorSadanandam, A
dc.contributor.authorKocher, HM
dc.date.accessioned2019-02-20T07:45:37Z
dc.date.issued2019-05
dc.identifier.citationThe Journal of pathology, 2019, 248 (1), pp. 51 - 65
dc.identifier.issn0022-3417
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3059
dc.identifier.eissn1096-9896
dc.identifier.doi10.1002/path.5224
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.
dc.formatPrint-Electronic
dc.format.extent51 - 65
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectTumor Cells, Cultured
dc.subjectStromal Cells
dc.subjectHumans
dc.subjectCarcinoma, Pancreatic Ductal
dc.subjectPancreatic Neoplasms
dc.subjectPrognosis
dc.subjectGene Expression Profiling
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectPhenotype
dc.subjectGenetic Heterogeneity
dc.subjectKaplan-Meier Estimate
dc.subjectPancreatic Stellate Cells
dc.subjectTumor Microenvironment
dc.subjectCancer-Associated Fibroblasts
dc.titleInter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma.
dc.typeJournal Article
dcterms.dateAccepted2018-12-18
rioxxterms.versionofrecord10.1002/path.5224
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of pathology
pubs.issue1
pubs.notesNot known
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.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-statusPublished
pubs.volume248
pubs.embargo.termsNot known
icr.researchteamSystems and Precision Cancer Medicineen_US
dc.contributor.icrauthorSadanandam, Angurajen


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