title: Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2-mediated Akt activation.
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.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fernandez-L
authors.forename: M
authors.initials: M
authors.lastname: Squatrito
authors.forename: P
authors.initials: P
authors.lastname: Northcott
authors.forename: A
authors.initials: A
authors.lastname: Awan
authors.forename: E C
authors.initials: EC
authors.lastname: Holland
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Z
authors.initials: Z
authors.lastname: Nahlé
authors.forename: A M
authors.initials: AM
authors.lastname: Kenney
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D004249:DNA Damage; D042822:Genomic Instability; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics* / Q000532:radiotherapy*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011836:Radiation Tolerance; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D007335:Insulin-Like Growth Factor II; D051057:Proto-Oncogene Proteins c-akt