STAT3 blockade inhibits a radiation-induced proneural-to-mesenchymal transition in glioma

Malignant progression is often associated with a mesenchymal phenotype and poor prognosis. To test whether radiotherapy 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. Radiation of primary proneural high-grade glioma cells derived from mouse and human tumors also induced a sustained cell-intrinsic mesenchymal transition, associated with increased invasiveness and resistance to the alkylating agent temozolomide. The transcription factor STAT3 was activated in response to irradiation, and blockade of STAT3 abrogated the mesenchymal transition and combination treatment of JAK2 inhibitors with radiation extended survival in mice. Our data suggest that clinical JAK2 inhibitors should be tested in conjunction with radiation in patients with proneural high-grade glioma, to block emergence of therapy-resistant mesenchymal tumors at relapse.