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dc.contributor.authorTumbarello, David Aen
dc.contributor.authorAndrews, Melissa Ren
dc.contributor.authorBrenton, Jamesen
dc.date.accessioned2016-11-03T14:50:24Z
dc.date.available2016-11-03T14:50:24Z
dc.date.issued2016-10-13en
dc.identifier.issn1932-6203
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/261018
dc.description.abstractTGFBI has been shown to sensitize ovarian cancer cells to the cytotoxic effects of paclitaxel via an integrin receptor-mediated mechanism that modulates microtubule stability. Herein, we determine that TGFBI localizes within organized fibrillar structures in mesothelial-derived ECM. We determined that suppression of SPARC expression by shRNA decreased the deposition of TGFBI in mesothelial-derived ECM, without affecting its overall protein expression or secretion. Conversely, overexpression of SPARC increased TGFBI deposition. A SPARC-YFP fusion construct expressed by the Met5a cell line co-localized with TGFBI in the cell-derived ECM. Interestingly, $\textit{in vitro}$ produced SPARC was capable of precipitating TGFBI from cell lysates dependent on an intact SPARC carboxy-terminus with $\textit{in vitro}$ binding assays verifying a direct interaction. The last 37 amino acids of SPARC were shown to be required for the TGFBI interaction while expression of a SPARC-YFP construct lacking this region (aa 1–256) did not interact and co-localize with TGFBI in the ECM. Furthermore, ovarian cancer cells have a reduced motility and decreased response to the chemotherapeutic agent paclitaxel when plated on ECM derived from mesothelial cells lacking SPARC compared to control mesothelial-derived ECM. In conclusion, SPARC regulates the fibrillar ECM deposition of TGFBI through a novel interaction, subsequently influencing cancer cell behavior.
dc.description.sponsorshipThis work was supported by Cancer Research UK and the University of Cambridge.
dc.languageEnglishen
dc.language.isoenen
dc.publisherPLOS
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleSPARC Regulates Transforming Growth Factor Beta Induced (TGFBI) Extracellular Matrix Deposition and Paclitaxel Response in Ovarian Cancer Cellsen
dc.typeArticle
dc.description.versionThis is the final version of the article. It first appeared from PLOS via https://doi.org/10.1371/journal.pone.0162698en
prism.numbere0162698en
prism.publicationDate2016en
prism.publicationNamePLOS ONEen
prism.volume11en
dc.identifier.doi10.17863/CAM.6085
dcterms.dateAccepted2016-08-26en
rioxxterms.versionofrecord10.1371/journal.pone.0162698en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-10-13en
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
dc.identifier.eissn1932-6203
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (CRUK-A15601)
cam.orpheus.successThu Jan 30 12:57:24 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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