DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification

C. V. Camacho, P. K. Todorova, M. C. Hardebeck, N. Tomimatsu, C. R. Gil del Alcazar, M. Ilcheva, B. Mukherjee, B. McEllin, V. Vemireddy, K. Hatanpaa, M. D. Story, A. A. Habib, V. V. Murty, R. Bachoo, S. Burma

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Glioblastomas (GBM) are highly radioresistant and lethal brain tumors. Ionizing radiation (IR)-induced DNA double-strand breaks (DSBs) are a risk factor for the development of GBM. In this study, we systematically examined the contribution of IR-induced DSBs to GBM development using transgenic mouse models harboring brain-targeted deletions of key tumor suppressors frequently lost in GBM, namely Ink4a, Ink4b, Arf and/or PTEN. Using low linear energy transfer (LET) X-rays to generate simple breaks or high LET HZE particles (Fe ions) to generate complex breaks, we found that DSBs induce high-grade gliomas in these mice which, otherwise, do not develop gliomas spontaneously. Loss of Ink4a and Arf was sufficient to trigger IR-induced glioma development but additional loss of Ink4b significantly increased tumor incidence. We analyzed IR-induced tumors for copy number alterations to identify oncogenic changes that were generated and selected for as a consequence of stochastic DSB events. We found Met amplification to be the most significant oncogenic event in these radiation-induced gliomas. Importantly, Met activation resulted in the expression of Sox2, a GBM cancer stem cell marker, and was obligatory for tumor formation. In sum, these results indicate that radiation-induced DSBs cooperate with loss of Ink4 and Arf tumor suppressors to generate high-grade gliomas that are commonly driven by Met amplification and activation.

Original languageEnglish (US)
Pages (from-to)1064-1072
Number of pages9
JournalOncogene
Volume34
Issue number8
DOIs
StatePublished - Feb 19 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Camacho, C. V., Todorova, P. K., Hardebeck, M. C., Tomimatsu, N., Gil del Alcazar, C. R., Ilcheva, M., Mukherjee, B., McEllin, B., Vemireddy, V., Hatanpaa, K., Story, M. D., Habib, A. A., Murty, V. V., Bachoo, R., & Burma, S. (2015). DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification. Oncogene, 34(8), 1064-1072. https://doi.org/10.1038/onc.2014.29