Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer

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dc.contributor.author Öhlund, Daniel
dc.contributor.author Handly-Santana, Abram
dc.contributor.author Biffi, Giulia
dc.contributor.author Elyada, Ela
dc.contributor.author Almeida, Ana S.
dc.contributor.author Ponz-Sarvise, Mariano
dc.contributor.author Corbo, Vincenzo
dc.contributor.author Oni, Tobiloba E.
dc.contributor.author Hearn, Stephen A.
dc.contributor.author Lee, Eun Jung
dc.contributor.author Chio, Iok In Christine
dc.contributor.author Hwang, Chang-Il
dc.contributor.author Tiriac, Herve
dc.contributor.author Baker, Lindsey A.
dc.contributor.author Engle, Dannielle D.
dc.contributor.author Feig, Christine
dc.contributor.author Kultti, Anne
dc.contributor.author Egeblad, Mikala
dc.contributor.author Fearon, Douglas T.
dc.contributor.author Crawford, James M.
dc.contributor.author Clevers, Hans
dc.contributor.author Park, Youngkyu
dc.contributor.author Tuveson, David A.
dc.date.accessioned 2018-06-15T11:47:20Z
dc.date.available 2018-06-15T11:47:20Z
dc.date.issued 2017
dc.identifier.citation Öhlund, 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.20162024 en
dc.identifier.volume 214
dc.identifier.issued 3
dc.identifier.startpage 579
dc.identifier.endpage 596
dc.identifier.issn 0022-1007
dc.identifier.uri http://hdl.handle.net/10468/6359
dc.identifier.doi 10.1084/jem.20162024
dc.description.abstract Pancreatic 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.sponsorship Cold 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Rockefeller University Press en
dc.relation.uri http://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.uri https://creativecommons.org/licenses/by/4.0/
dc.subject Stellate cells en
dc.subject Ductal adenocarcinoma en
dc.subject Tumor microenvironment en
dc.subject RNA-seq en
dc.subject Stroma en
dc.subject Progression en
dc.subject Interleukin-6 en
dc.subject Gemcitabine en
dc.subject Resistance en
dc.subject Differentiation en
dc.title Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Ana Almeida, APC Microbiome Institute, University College Cork, Cork, Ireland. +353-21-490-3000. Email: a.almeida@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder Nancy Gay fellowship
dc.contributor.funder National Cancer Institute
dc.contributor.funder Damon Runyon Cancer Research Foundation
dc.contributor.funder Associazione Italiana per la Ricerca sul Cancro
dc.contributor.funder Ministero della Salute
dc.contributor.funder European Molecular Biology Organization
dc.contributor.funder Weizmann Institute of Science
dc.contributor.funder Human Frontiers Science Program
dc.contributor.funder Cancer Research Foundation in Northern Sweden
dc.contributor.funder Västerbotten Läns Landsting
dc.contributor.funder Svenska Läkaresällskapet
dc.contributor.funder Kempestiftelserna
dc.contributor.funder Vetenskapsrådet
dc.contributor.funder Precision Medicine Research Associates
dc.contributor.funder U.S. Department of Defense
dc.contributor.funder Starr Foundation
dc.contributor.funder KWF Kankerbestrijding
dc.contributor.funder Stand Up To Cancer
dc.contributor.funder National Institutes of Health
dc.contributor.funder Lustgarten Foundation
dc.contributor.funder National Cancer Institute
dc.contributor.funder Cold Spring Harbor
dc.description.status Peer reviewed
dc.identifier.journaltitle Journal of Experimental Medicine en
dc.internal.IRISemailaddress a.almeida@ucc.ie en


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© 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/) Except where otherwise noted, this item's license is described as © 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/)
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