STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma.
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.
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.
Jasmine
J
Lau
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.
Shirin
S
Ilkhanizadeh
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.
Susan
S
Wang
Department of Surgery and Center for Bioengineering and Tissue Regeneration, University of California, San Francisco, San Francisco, California.
Yekaterina A
YA
Miroshnikova
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.
Nicolas A
NA
Salvatierra
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.
Robyn A
RA
Wong
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.
Christin
C
Schmidt
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.
Valerie M
VM
Weaver
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.
William A
WA
Weiss
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.
Anders I
AI
Persson
D064591:Allografts; D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011827:Radiation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015415:Biomarkers; D050796:STAT3 Transcription Factor; D053614:Janus Kinase 2