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Cancer Res. 2015 Oct 15;75(20):4302-11. doi: 10.1158/0008-5472.CAN-14-3331. Epub 2015 Aug 17.

STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma.

Author information

1
Department of Pediatrics, University of California, San Francisco, San Francisco, California. Department of Neurology, Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore.
2
Department of Pediatrics, University of California, San Francisco, San Francisco, California. Department of Neurology, Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
3
Department of Neurology, Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Sandler Neurosciences Center, University of California, San Francisco, San Francisco, California.
4
Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, California.
5
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, California. Departments of Anatomy and Bioengineering and Therapeutic Sciences, and Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California.
6
Department of Pediatrics, University of California, San Francisco, San Francisco, California. Department of Neurology, Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. anders.persson@ucsf.edu waweiss@gmail.com.
7
Department of Neurology, Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Sandler Neurosciences Center, University of California, San Francisco, San Francisco, California. anders.persson@ucsf.edu waweiss@gmail.com.

Abstract

High grade gliomas (HGG) are classified into four subgroups based on transcriptional signatures and phenotypic characteristics. In particular, the proneural-to-mesenchymal transition (PMT) is associated with increased malignancy, poor prognosis, and disease recurrence, but the underlying causes of PMT are still unclear. In this study, we investigated whether radiotherapy promotes PMT using a genetically engineered mouse model of proneural HGG. We found that cranial ionizing radiation induced robust and durable PMT in tumors. Additionally, we isolated primary proneural HGG cells from mouse and human tumors and demonstrate that radiation induced a sustained cell-intrinsic mesenchymal transition associated with increased invasiveness and resistance to the alkylating agent temozolomide. Expectedly, irradiation-induced PMT was also associated with activation of the STAT3 transcription factor, and the combination of STAT3 blockade using JAK2 inhibitors with radiation abrogated the mesenchymal transition and extended survival of mice. Taken together, our data suggest that clinical JAK2 inhibitors should be tested in conjunction with radiation in patients with proneural HGG as a new strategy for blocking the emergence of therapy-resistant mesenchymal tumors at relapse.

PMID:
26282165
PMCID:
PMC4609277
DOI:
10.1158/0008-5472.CAN-14-3331
[Indexed for MEDLINE]
Free PMC Article

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