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

Zhukova, N and Ramaswamy, V and Remke, M and Martin, DC and Castelo-Branco, P and Zhang, CH and Fraser, M and Tse, K and Poon, R and Shih, DJH and Baskin, B and Ray, PN and Bouffet, E and Dirks, P and von Bueren, AO and Pfaff, E and Korshunov, A and Jones, DTW and Northcott, PA and Kool, M and Pugh, TJ and Pomeroy, SL and Cho, YJ and Pietsch, T and Gessi, M and Rutkowski, S and Bognár, L and Cho, BK and Eberhart, CG and Conter, CF and Fouladi, M and French, PJ and Grajkowska, WA and Gupta, N and Hauser, P and Jabado, N and Vasiljevic, A and Jung, S and Kim, SK and Klekner, A and Kumabe, T and Lach, B and Leonard, JR and Liau, LM and Massimi, L and Pollack, IF and Ra, YS and Rubin, JB and Van Meir, EG and Wang, KC and Weiss, WA and Zitterbart, K and Bristow, RG and Alman, B and Hawkins, CE and Malkin, D and Clifford, SC and Pfister, SM and Taylor, MD and Tabori, U (2014) WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma. Acta Neuropathologica Communications, 2 (1).

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Abstract

TP53 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, β-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 γH2AX 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.

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Zhukova, N Ramaswamy, V Remke, M Martin, DC Castelo-Branco, P Zhang, CH Fraser, M Tse, K Poon, R Shih, DJH Baskin, B Ray, PN Bouffet, E Dirks, P von Bueren, AO Pfaff, E Korshunov, A Jones, DTW Northcott, PA Kool, M Pugh, TJ Pomeroy, SL Cho, YJ Pietsch, T Gessi, M Rutkowski, S Bognár, L Cho, BK Eberhart, CG Conter, CF Fouladi, M French, PJ Grajkowska, WA Gupta, N Hauser, P Jabado, N Vasiljevic, A Jung, S Kim, SK Klekner, A Kumabe, T Lach, B Leonard, JR Liau, LM Massimi, L Pollack, IF ipollack@pitt.edu IPOLLACK Ra, YS Rubin, JB Van Meir, EG Wang, KC Weiss, WA Zitterbart, K Bristow, RG Alman, B Hawkins, CE Malkin, D Clifford, SC Pfister, SM Taylor, MD Tabori, U
Date:	27 January 2014
Date Type:	Publication
Journal or Publication Title:	Acta Neuropathologica Communications
Volume:	2
Number:	1
DOI or Unique Handle:	10.1186/s40478-014-0174-y
Schools and Programs:	School of Medicine > Neurological Surgery
Refereed:	Yes
Date Deposited:	22 Dec 2016 15:24
Last Modified:	30 Mar 2021 14:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29432

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