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dc.contributor.authorSomerville, Tim DD
dc.contributor.authorBiffi, Giulia
dc.contributor.authorDaßler-Plenker, Juliane
dc.contributor.authorHur, Stella K
dc.contributor.authorHe, Xue-Yan
dc.contributor.authorVance, Krysten E
dc.contributor.authorMiyabayashi, Koji
dc.contributor.authorXu, Yali
dc.contributor.authorMaia-Silva, Diogo
dc.contributor.authorKlingbeil, Olaf
dc.contributor.authorDemerdash, Osama E
dc.contributor.authorPreall, Jonathan B
dc.contributor.authorHollingsworth, Michael A
dc.contributor.authorEgeblad, Mikala
dc.contributor.authorTuveson, David A
dc.contributor.authorVakoc, Christopher R
dc.date.accessioned2020-05-06T02:08:07Z
dc.date.available2020-05-06T02:08:07Z
dc.date.issued2020-04-24
dc.date.submitted2019-11-06
dc.identifier.other53381
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/305042
dc.descriptionFunder: Pershing Square Foundation; FundRef: http://dx.doi.org/10.13039/100010304
dc.descriptionFunder: Lustgarten Foundation; FundRef: http://dx.doi.org/10.13039/100005979
dc.descriptionFunder: The Cold Spring Harbor Laboratory and Northwell Health Affiliation
dc.descriptionFunder: Thompson Family Foundation
dc.descriptionFunder: Simons Foundation; FundRef: http://dx.doi.org/10.13039/100000893
dc.description.abstractA highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A and CXCL1 as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch Article
dc.subjectCancer Biology
dc.subjectHuman Biology and Medicine
dc.subjectTP63
dc.subjectinflammation
dc.subjectcancer-associated fibroblasts
dc.subjectpancreatic cancer
dc.subjecttrans-differentiation
dc.subjectsquamous
dc.subjectHuman
dc.subjectMouse
dc.titleSquamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation
dc.typeArticle
dc.date.updated2020-05-06T02:08:06Z
prism.publicationNameeLife
prism.volume9
dc.identifier.doi10.17863/CAM.52123
dcterms.dateAccepted2020-04-23
rioxxterms.versionofrecord10.7554/elife.53381
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Sawyers, Charles L
datacite.contributor.supervisorsenior_editor: Ojala, Päivi M
dc.contributor.orcidSomerville, Tim DD [0000-0002-6295-6126]
dc.contributor.orcidVakoc, Christopher R [0000-0002-1158-7180]
dc.identifier.eissn2050-084X
pubs.funder-project-idNew York State Department of Health (C150158)
pubs.funder-project-idNational Cancer Institute (5P01CA013106-Project 4)
pubs.funder-project-idNational Cancer Institute (CA229699)
pubs.funder-project-idPancreatic Cancer Action Network (16-20-25-VAKO)
pubs.funder-project-idNational Cancer Institute (5P30CA45508)
pubs.funder-project-idNational Cancer Institute (5P50CA101955)
pubs.funder-project-idNational Cancer Institute (P20CA192996)
pubs.funder-project-idNational Cancer Institute (U10CA180944)
pubs.funder-project-idNational Cancer Institute (U01CA210240)
pubs.funder-project-idNational Cancer Institute (U01CA224013)
pubs.funder-project-idNational Cancer Institute (1R01CA188134)
pubs.funder-project-idNational Cancer Institute (1R01CA190092)
pubs.funder-project-idState of New York (C150158)
pubs.funder-project-idHuman Frontier Science Program (LT000195/2015 L)
pubs.funder-project-idEMBO (ALTF 1203–2014)
pubs.funder-project-idDeutsche Forschungsgemeinschaft (DA 2249/1–1)
pubs.funder-project-idDeutsche Forschungsgemeinschaft (KL 3228/1–1)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)