title: Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway.
abstract: While treatments that induce DNA damage are commonly used as anticancer therapies, the mechanisms through which DNA damage produces a therapeutic response are incompletely understood. Here we have tested whether medulloblastomas must be competent for apoptosis to be sensitive to radiotherapy. Whether apoptosis is required for radiation sensitivity has been controversial. Medulloblastoma, the most common malignant brain tumor in children, is a biologically heterogeneous set of tumors typically sensitive to radiation and chemotherapy; 80% of medulloblastoma patients survive long-term after treatment. We used functional genetic studies to determine whether the intrinsic apoptotic pathway is required for radiation to produce a therapeutic response in mice with primary, Shh-driven medulloblastoma. We found that cranial radiation extended the survival of medulloblastoma-bearing mice and induced widespread apoptosis. Expression analysis and conditional deletion studies showed that Trp53 (p53) was the predominant transcriptional regulator activated by radiation and was strictly required for treatment response. Deletion of Bax, which blocked apoptosis downstream of p53, was sufficient to render tumors radiation resistant. In apoptosis-incompetent, Bax-deleted tumors, radiation activated p53-dependent transcription without provoking cell death and caused two discrete populations to emerge. Most radiated tumor cells underwent terminal differentiation. Perivascular cells, however, quickly resumed proliferation despite p53 activation, behaved as stem cells, and rapidly drove recurrence. These data show that radiation must induce apoptosis in tumor stem cells to be effective. Mutations that disable the intrinsic apoptotic pathways are sufficient to impart radiation resistance. We suggest that medulloblastomas are typically sensitive to DNA-damaging therapies, because they retain apoptosis competence. Cancer Res; 76(11); 3211-23. ©2016 AACR.
authors.affiliation: UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Crowther
authors.affiliation: UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ocasio
authors.affiliation: Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Jessica
authors.initials: J
authors.lastname: Meidinger
authors.affiliation: Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Wu
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Deal
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Sha X
authors.initials: SX
authors.lastname: Chang
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmid
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Ian
authors.initials: I
authors.lastname: Davis
authors.affiliation: UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. gershont@neurology.unc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D015153:Blotting, Western; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D004195:Disease Models, Animal; D005720:Gamma Rays; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger