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

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

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...

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Main Authors: Camacho, Cristel V., Todorova, Pavlina K., Gillam, Molly C., Tomimatsu, Nozomi, del Alcazar, Carlos R Gil, Ilcheva, Mariya, Mukherjee, Bipasha, McEllin, Brian, Vemireddy, Vamsidhara, Hatanpaa, Kimmo, Story, Michael D., Habib, Amyn A., Murty, Vundavalli V., Bachoo, Robert, Burma, Sandeep
Format: Online
Language:English
Published: 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167163/
id pubmed-4167163
recordtype oai_dc
spelling pubmed-41671632015-08-19 DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification Camacho, Cristel V. Todorova, Pavlina K. Gillam, Molly C. Tomimatsu, Nozomi del Alcazar, Carlos R Gil Ilcheva, Mariya Mukherjee, Bipasha McEllin, Brian Vemireddy, Vamsidhara Hatanpaa, Kimmo Story, Michael D. Habib, Amyn A. Murty, Vundavalli V. Bachoo, Robert Burma, Sandeep Article 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 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 (CNAs) 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 expression of Sox2, a GBM cancer stem cell (CSC) 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. 2014-03-17 2015-02-19 /pmc/articles/PMC4167163/ /pubmed/24632607 http://dx.doi.org/10.1038/onc.2014.29 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Camacho, Cristel V.
Todorova, Pavlina K.
Gillam, Molly C.
Tomimatsu, Nozomi
del Alcazar, Carlos R Gil
Ilcheva, Mariya
Mukherjee, Bipasha
McEllin, Brian
Vemireddy, Vamsidhara
Hatanpaa, Kimmo
Story, Michael D.
Habib, Amyn A.
Murty, Vundavalli V.
Bachoo, Robert
Burma, Sandeep
spellingShingle Camacho, Cristel V.
Todorova, Pavlina K.
Gillam, Molly C.
Tomimatsu, Nozomi
del Alcazar, Carlos R Gil
Ilcheva, Mariya
Mukherjee, Bipasha
McEllin, Brian
Vemireddy, Vamsidhara
Hatanpaa, Kimmo
Story, Michael D.
Habib, Amyn A.
Murty, Vundavalli V.
Bachoo, Robert
Burma, Sandeep
DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
author_facet Camacho, Cristel V.
Todorova, Pavlina K.
Gillam, Molly C.
Tomimatsu, Nozomi
del Alcazar, Carlos R Gil
Ilcheva, Mariya
Mukherjee, Bipasha
McEllin, Brian
Vemireddy, Vamsidhara
Hatanpaa, Kimmo
Story, Michael D.
Habib, Amyn A.
Murty, Vundavalli V.
Bachoo, Robert
Burma, Sandeep
author_sort Camacho, Cristel V.
title DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
title_short DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
title_full DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
title_fullStr DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
title_full_unstemmed DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification
title_sort dna double-strand breaks cooperate with loss of ink4 and arf tumor suppressors to generate glioblastomas with frequent met amplification
description 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 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 (CNAs) 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 expression of Sox2, a GBM cancer stem cell (CSC) 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.
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167163/
_version_ 1613134900905377792

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