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

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Authors	ZHUKOVA Nataliya RAMASWAMY Vijay REMKE Marc MARTIN Dianna C CASTELO-BRANCO Pedro ZHANG Cindy H FRASER Michael TSE Ken POON Raymond SHIH David JH BASKIN Berivan RAY Peter N BOUFFET Eric DIRKS Peter BUEREN Andre O von PFAFF Elke KORSHUNOV Andrey JONES David TW NORTHCOTT Paul A KOOL Marcel PUGH Trevor J POMEROY Scott L CHO Yoon-Jae PIETSCH Torsten GESSI Marco RUTKOWSKI Stefan BOGNÁR Laszlo CHO Byung-Kyu EBERHART Charles G CONTER Cecile Faure FOULADI Maryam FRENCH Pim J GRAJKOWSKA Wieslawa A GUPTA Nalin HAUSER Peter JABADO Nada VASILJEVIC Alexandre JUNG Shin KIM Seung-Ki KLEKNER Almos KUMABE Toshihiro LACH Boleslaw LEONARD Jeffrey R LIAU Linda M MASSIMI Luca POLLACK Ian F RA Young Shin RUBIN Joshua B MEIR Erwin G Van WANG Kyu-Chang WEISS William A ZITTERBART Karel BRISTOW Robert G ALMAN Benjamin HAWKINS Cynthia E MALKIN David CLIFFORD Steven C PFISTER Stefan M TAYLOR Michael D TABORI Uri
Year of publication	2014
Type	Article in Periodical
Magazine / Source	Acta Neuropathologica Communications
MU Faculty or unit	Faculty of Medicine
Citation
Doi	http://dx.doi.org/10.1186/s40478-014-0174-y
Field	Oncology and hematology
Keywords	TP53 mutation; medulloblastoma
Description	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, 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 gammaH2AX 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.
Related projects:	Centrum experimentální biomedicíny