Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

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dc.contributor.authorÖhlund, Daniel
dc.contributor.authorHandly-Santana, Abram
dc.contributor.authorBiffi, Giulia
dc.contributor.authorElyada, Ela
dc.contributor.authorAlmeida, Ana S.
dc.contributor.authorPonz-Sarvise, Mariano
dc.contributor.authorCorbo, Vincenzo
dc.contributor.authorOni, Tobiloba E.
dc.contributor.authorHearn, Stephen A.
dc.contributor.authorLee, Eun Jung
dc.contributor.authorChio, Iok In Christine
dc.contributor.authorHwang, Chang-Il
dc.contributor.authorTiriac, Herve
dc.contributor.authorBaker, Lindsey A.
dc.contributor.authorEngle, Dannielle D.
dc.contributor.authorFeig, Christine
dc.contributor.authorKultti, Anne
dc.contributor.authorEgeblad, Mikala
dc.contributor.authorFearon, Douglas T.
dc.contributor.authorCrawford, James M.
dc.contributor.authorClevers, Hans
dc.contributor.authorPark, Youngkyu
dc.contributor.authorTuveson, David A.
dc.contributor.funderNancy Gay fellowship
dc.contributor.funderNational Cancer Institute
dc.contributor.funderDamon Runyon Cancer Research Foundation
dc.contributor.funderAssociazione Italiana per la Ricerca sul Cancro
dc.contributor.funderMinistero della Salute
dc.contributor.funderEuropean Molecular Biology Organization
dc.contributor.funderWeizmann Institute of Science
dc.contributor.funderHuman Frontiers Science Program
dc.contributor.funderCancer Research Foundation in Northern Sweden
dc.contributor.funderVästerbotten Läns Landsting
dc.contributor.funderSvenska Läkaresällskapet
dc.contributor.funderKempestiftelserna
dc.contributor.funderVetenskapsrådet
dc.contributor.funderPrecision Medicine Research Associates
dc.contributor.funderU.S. Department of Defense
dc.contributor.funderStarr Foundation
dc.contributor.funderKWF Kankerbestrijding
dc.contributor.funderStand Up To Cancer
dc.contributor.funderNational Institutes of Health
dc.contributor.funderLustgarten Foundation
dc.contributor.funderNational Cancer Institute
dc.contributor.funderCold Spring Harbor
dc.date.accessioned2018-06-15T11:47:20Z
dc.date.available2018-06-15T11:47:20Z
dc.date.issued2017
dc.description.abstractPancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of a-smooth muscle actin (alpha SMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated aSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.en
dc.description.sponsorshipCold Spring Harbor (Cancer Center Support Grant (CCSG); Laboratory Association); National Institutes of Health (5P30CA45508-26; 5P50CA101955-07; 1U10CA180944-02; 5U01CA168409-5; 1R01CA188134; 1R01CA190092-03; R50CA311506-01; CA101955 UAB/UMN SPORE; 5T32CA148056; F32CA192904); Starr Foundation (I7-A718); U.S. Department of Defense(W81XWH-13-PRCRP-IA);Vetenskapsrådet (537-2013-7277); Kempestiftelserna (JCK-1301); Svenska Läkaresällskapet (SLS-326921, SLS-250831, SLS175991, SLS-591551); Västerbotten Läns Landsting (ALFVLL269081, VLL242121, VLL322391, VLL400421, VLL493371, VLL582681); Cancer Research Foundation in Northern Sweden (AMP15-793, LP11-1927); Human Frontiers Science Program (LT000403/2014, LT000195/2015-L, LT000190/2013); Weizmann Institute of Science (Women in Science award); European Molecular Biology Organization (ALTF 1203-2014); Ministero della Salute (FIRB - RBAP10AHJ); Associazione Italiana Ricerca Cancro (18718); Damon Runyon Cancer Research Foundation (DRG-2165-13); National Cancer Institute (1K99CA204725-01A1)en
dc.description.statusPeer reviewed
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationÖhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., Chio, I. I. C., Hwang, C.-I., Tiriac, H., Baker, L. A., Engle, D. D., Feig, C., Kultti, A., Egeblad, M., Fearon, D. T., Crawford, J. M., Clevers, H., Park, Y. and Tuveson, D. A. (2017) 'Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer', Journal of Experimental Medicine, 214(3), pp. 579-596. doi: 10.1084/jem.20162024en
dc.identifier.doi10.1084/jem.20162024
dc.identifier.endpage596
dc.identifier.issn0022-1007
dc.identifier.issued3
dc.identifier.journaltitleJournal of Experimental Medicineen
dc.identifier.startpage579
dc.identifier.urihttps://hdl.handle.net/10468/6359
dc.identifier.volume214
dc.language.isoenen
dc.publisherRockefeller University Pressen
dc.relation.urihttp://jem.rupress.org/content/214/3/579
dc.rights© 2017, Öhlund et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectStellate cellsen
dc.subjectDuctal adenocarcinomaen
dc.subjectTumor microenvironmenten
dc.subjectRNA-seqen
dc.subjectStromaen
dc.subjectProgressionen
dc.subjectInterleukin-6en
dc.subjectGemcitabineen
dc.subjectResistanceen
dc.subjectDifferentiationen
dc.titleDistinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic canceren
dc.typeArticle (peer-reviewed)en
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