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

Oncogene volume 34, pages 1064–1072 (2015)Cite this article

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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.

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Acknowledgements

SB is supported by grants from the National Aeronautics and Space Administration (NNX13AI13G), National Institutes of Health (RO1 CA149461) and the Cancer Prevention and Research Institute of Texas (RP100644). AAH is supported by a National Institutes of Health grant (R01 NS062080). MCH is supported by a National Institute of General Medical Sciences training grant 5T32GM008203 in cellular and molecular biology. CVC was supported by a NCI training grant (T32CA124334). CVC completed this work in partial fulfillment of the requirements for her PhD degree. We thank Dr Chaitanya Nirodi for valuable advice on cloning and lentivirus production strategies. We also thank the support staff at the NASA Space Radiation Research Laboratory, Brookhaven National Laboratory, Upton, NY, USA, for facilitating particle radiation experiments.

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  1. C V Camacho

    Present address: 6Current address: St Jude Children’s Research Hospital, Memphis, TN, USA.,

Authors and Affiliations

  1. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA,

    C V Camacho, P K Todorova, M C Hardebeck, N Tomimatsu, C R Gil del Alcazar, M Ilcheva, B Mukherjee, M D Story & S Burma

  2. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA,

    B McEllin, V Vemireddy, A A Habib & R Bachoo

  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    K Hatanpaa

  4. VA North Texas Health Care System, Dallas, TX, USA

    A A Habib

  5. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA

    V V Murty

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Camacho, C., Todorova, P., Hardebeck, M. et al. DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification. Oncogene 34, 1064–1072 (2015). https://doi.org/10.1038/onc.2014.29

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