UCSF

Malignant progression in glioma and other cancers is associated with the acquisition of a mesenchymal phenotype and with poor prognosis. To test if radiotherapy, as standard of care in glioma, promotes a mesenchymal transition, we irradiated proneural tumors arising in a genetically engineered mouse model for high-grade glioma. Cranial ionizing radiation induced a robust and durable proneural-to-mesenchymal transition in tumors in vivo. Radiation of primary proneural glioma cells derived from mouse and human tumors also induced a cell-intrinsic and sustained proneural-to-mesenchymal transition in vitro. Following irradiation, glioma cells undergoing a mesenchymal transition displayed increased resistance to alkylating chemotherapy, and showed increased invasion and motility. The transcription factor STAT3 has been identified as a master regulator of the mesenchymal transcriptional network in high-grade glioma tumors. We demonstrate that cell-intrinsic activation of STAT3 activation mediates a proneural-to- mesenchymal transition that confers radiation resistance in glioma. Pretreatment with inhibitors of JAK2, an upstream kinase that activates STAT3, blocked this mesenchymal transition. Our results suggest that therapeutic blockade of the JAK2-STAT3 pathway concurrent with current therapy in patients with proneural high-grade glioma may block the emergence of therapy-resistant mesenchymal tumors at relapse.