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Brachyury Is associated with glioma differentiation and response to temozolomide

2020-10Journal article Restricted access
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dc.contributor.authorPinto, Filipe
dc.contributor.authorCosta, Angela M.
dc.contributor.authorAndrade, Raquel P.
dc.contributor.authorReis, Rui Manuel
dc.date.accessioned2021-06-24T11:35:22Z
dc.date.available2021-06-24T11:35:22Z
dc.date.issued2020-10
dc.description.abstractGlioblastomas (GBMs) are the most aggressive tumor type of the central nervous system, mainly due to their high invasiveness and innate resistance to radiotherapy and chemotherapy, with temozolomide (TMZ) being the current standard therapy. Recently, brachyury was described as a novel tumor suppressor gene in gliomas, and its loss was associated with increased gliomagenesis. Here, we aimed to explore the role of brachyury as a suppressor of glioma invasion, stem cell features, and resistance to TMZ. Using gene-edited glioma cells to overexpress brachyury, we found that brachyury-positive cells exhibit reduced invasive and migratory capabilities and stem cell features. Importantly, these brachyury-expressing cells have increased expression of differentiation markers, which corroborates the results from human glioma samples andin vivotumors. Glioma cells treated with retinoic acid increased the differentiation status with concomitant increased expression of brachyury. We then selected TMZ-resistant (SNB-19) and TMZ-responsive (A172 and U373) cell lines to evaluate the role of brachyury in the response to TMZ treatment. We observed that both exogenous and endogenous brachyury activation, through overexpression and retinoic acid treatment, are associated with TMZ sensitization in glioma-resistant cell lines. In this study, we demonstrate that brachyury expression can impair aggressive glioma features associated with treatment resistance. Finally, we provide the first evidence that brachyury can be a potential therapeutic target in GBM patients who do not respond to conventional chemotherapeutic drugs.
dc.description.sponsorshipICVS
dc.description.sponsorshipBarretos Cancer Hospital internal research founds
dc.description.sponsorshipPortuguese FundacAo para a Ciencia e a Tecnologia (FCT)Portuguese Foundation for Science and Technology [PTDC/BEX-BID/5410/2014, UID/BIM/04773/2013 CBMR, PTDC/SAU-TOX/114549/2009-FCOMP-01-0124-FEDER-016057, PTDC/SAU-ONC/115513/2009-FCOMP-01-0124-FEDER-015949, PTDC/MED-ONC/31423/2017-POCI-01-0145-FEDER-031423]
dc.description.sponsorshipProject ON.2 SR&TD Integrated Program [NORTE-07-0124-FEDER-000017]
dc.description.sponsorshipPrograma Operacional Regional do Norte (ON.2-O Novo Norte), Quadro de Referencia Estrategico Nacional (QREN), Fundo Europeu de Desenvolvimento Regional (FEDER)
dc.description.sponsorshipBrazilian FAPESP grant [2012/19590-0]
dc.description.sponsorshipFCTPortuguese Foundation for Science and TechnologyEuropean Commission
dc.description.sponsorshipFundo Social Europeu-FSEEuropean Social Fund (ESF) [SFRH/BD/81369/2011, SFRH/BPD/115730/2016]
dc.description.sponsorship[PTDC/SAU-TOX/114549/2009]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1007/s13311-020-00911-9
dc.identifier.issn1933-7213
dc.identifier.urihttp://hdl.handle.net/10400.1/16418
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSpringer
dc.subjectGliomas
dc.subjectCrachyury
dc.subjectEMT
dc.subjectStem
dc.subjectTemozolomide
dc.subjectTherapy
dc.subjectTBXT
dc.subjectPharmacology & pharmacy
dc.subject.otherNeurosciences & Neurology
dc.titleBrachyury Is associated with glioma differentiation and response to temozolomide
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage2027
oaire.citation.issue4
oaire.citation.startPage2015
oaire.citation.titleNeurotherapeutics
oaire.citation.volume17
person.familyNameAndrade
person.givenNameRaquel
person.identifier.ciencia-id2312-360B-227A
person.identifier.orcid0000-0002-0397-5917
person.identifier.scopus-author-id7103114918
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublicationf2d3fc39-a8f6-4d83-9e60-2e2fdfbc2b4a
relation.isAuthorOfPublication.latestForDiscoveryf2d3fc39-a8f6-4d83-9e60-2e2fdfbc2b4a

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