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Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation

Oncogene volume 31, pages 1923–1937 (2012)Cite this article

Abstract

Radiation therapy remains the standard of care for many cancers, including the malignant pediatric brain tumor medulloblastoma. Radiation leads to long-term side effects, whereas radioresistance contributes to tumor recurrence. Radio-resistant medulloblastoma cells occupy the perivascular niche. They express Yes-associated protein (YAP), a Sonic hedgehog (Shh) target markedly elevated in Shh-driven medulloblastomas. Here we report that YAP accelerates tumor growth and confers radioresistance, promoting ongoing proliferation after radiation. YAP activity enables cells to enter mitosis with un-repaired DNA through driving insulin-like growth factor 2 (IGF2) expression and Akt activation, resulting in ATM/Chk2 inactivation and abrogation of cell cycle checkpoints. Our results establish a central role for YAP in counteracting radiation-based therapies and driving genomic instability, and indicate the YAP/IGF2/Akt axis as a therapeutic target in medulloblastoma.

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Acknowledgements

We are grateful to Martine Roussel and her group at St Jude Children's Research Hospital for training and advice on MBC culture and intracranial implantation. AF-L received support from the Spanish Ministry of Education, the Charles H Revson Foundation and the Childhood Brain Tumor Foundation. This work was supported by grants to AMK from the Alex's Lemonade Stand Foundation, National Brain Tumor Society, James S McDonnell Foundation and the NIH (NINDS R01NS061070).

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Authors and Affiliations

  1. Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    A Fernandez-L, M Squatrito & E C Holland

  2. Division of Neurosurgery, Program in Developmental and Stem cell Biology, Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    P Northcott & M D Taylor

  3. Departments of Neurosurgery and Cancer Biology, Vanderbilt University, Nashville, TN, USA

    A Awan, Z Nahlé & A M Kenney

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Correspondence to A M Kenney.

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Fernandez-L, A., Squatrito, M., Northcott, P. et al. Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation. Oncogene 31, 1923–1937 (2012). https://doi.org/10.1038/onc.2011.379

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