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WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

2014Journal article Open access
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dc.contributor.authorZhukova, Nataliya
dc.contributor.authorRamaswamy, Vijay
dc.contributor.authorRemke, Marc
dc.contributor.authorMartin, Dianna C.
dc.contributor.authorCastelo-Branco, Pedro
dc.contributor.authorZhang, Cindy H.
dc.contributor.authorFraser, Michael
dc.contributor.authorTse, Ken
dc.contributor.authorPoon, Raymond
dc.contributor.authorShih, David J. H.
dc.contributor.authorBaskin, Berivan
dc.contributor.authorRay, Peter N.
dc.contributor.authorBouffet, Eric
dc.contributor.authorDirks, Peter
dc.contributor.authorVon Bueren, Andre O.
dc.contributor.authorPfaff, Elke
dc.contributor.authorKorshunov, Andrey
dc.contributor.authorJones, David T. W.
dc.contributor.authorNorthcott, Paul A.
dc.contributor.authorKool, Marcel
dc.contributor.authorPugh, Trevor J.
dc.contributor.authorPomeroy, Scott L.
dc.contributor.authorCho, Yoon-Jae
dc.contributor.authorPietsch, Torsten
dc.contributor.authorGessi, Marco
dc.contributor.authorRutkowski, Stefan
dc.contributor.authorBognar, Laszlo
dc.contributor.authorCho, Byung-Kyu
dc.contributor.authorEberhart, Charles G.
dc.contributor.authorConter, Cecile Faure
dc.contributor.authorFouladi, Maryam
dc.contributor.authorFrench, Pim J.
dc.contributor.authorGrajkowska, Wieslawa A.
dc.contributor.authorGupta, Nalin
dc.contributor.authorHauser, Peter
dc.contributor.authorJabado, Nada
dc.contributor.authorVasiljevic, Alexandre
dc.contributor.authorJung, Shin
dc.contributor.authorKim, Seung-Ki
dc.contributor.authorKlekner, Almos
dc.contributor.authorKumabe, Toshihiro
dc.contributor.authorLach, Boleslaw
dc.contributor.authorLeonard, Jeffrey R.
dc.contributor.authorLiau, Linda M.
dc.contributor.authorMassimi, Luca
dc.contributor.authorPollack, Ian F.
dc.contributor.authorRa, Young Shin
dc.contributor.authorRubin, Joshua B.
dc.contributor.authorVan Meir, Erwin G.
dc.contributor.authorWang, Kyu-Chang
dc.contributor.authorWeiss, William A.
dc.contributor.authorZitterbart, Karel
dc.contributor.authorBristow, Robert G.
dc.contributor.authorAlman, Benjamin
dc.contributor.authorHawkins, Cynthia E.
dc.contributor.authorMalkin, David
dc.contributor.authorClifford, Steven C.
dc.contributor.authorPfister, Stefan M.
dc.contributor.authorTaylor, Michael D.
dc.contributor.authorTabori, Uri
dc.date.accessioned2018-12-07T14:58:29Z
dc.date.available2018-12-07T14:58:29Z
dc.date.issued2014
dc.description.abstractTP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
dc.description.sponsorshipB.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183]
dc.identifier.doi10.1186/s40478-014-0174-y
dc.identifier.issn2051-5960
dc.identifier.urihttp://hdl.handle.net/10400.1/12046
dc.language.isoeng
dc.peerreviewedyes
dc.publisherBMC
dc.titleWNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
dc.typejournal article
dspace.entity.typePublication
oaire.citation.startPage174
oaire.citation.titleActa Neuropathologica Communications
oaire.citation.volume2
person.familyNameCastelo-Branco
person.givenNamePedro
person.identifier.ciencia-idE015-7F8F-5CA1
person.identifier.orcid0000-0002-3453-3978
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublicationbb25b5ad-1769-42be-a7d3-8fe76215aa23
relation.isAuthorOfPublication.latestForDiscoverybb25b5ad-1769-42be-a7d3-8fe76215aa23

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