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

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, Kimmo J.; Story, M. D.; Habib, A. A.; Vundavalli, Murty V.; Bachoo, R.; Burma, S.

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.


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Pathology and Cell Biology
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September 30, 2019