RESUMO
Intratumoral heterogeneity is a hallmark of glioblastoma (GBM) tumors, thought to negatively influence therapeutic outcome. Previous studies showed that mesenchymal tumors have a worse outcome than the proneural subtype. Here we focus on STAT3 as its activation precedes the proneural-mesenchymal transition. We first establish a STAT3 gene signature that stratifies GBM patients into STAT3-high and -low cohorts. STAT3 inhibitor treatment selectively mitigates STAT3-high cell viability and tumorigenicity in orthotopic mouse xenograft models. We show the mechanism underlying resistance in STAT3-low cells by combining STAT3 signature analysis with kinome screen data on STAT3 inhibitor-treated cells. This allows us to draw connections between kinases affected by STAT3 inhibitors, their associated transcription factors and target genes. We demonstrate that dual inhibition of IGF-1R and STAT3 sensitizes STAT3-low cells and improves survival in mice. Our study underscores the importance of serially profiling tumors so as to accurately target individuals who may demonstrate molecular subtype switching.
Assuntos
Predisposição Genética para Doença/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Animais , Sobrevivência Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Imidazóis/farmacologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Camundongos , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Temozolomida/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: We explore the role of an elevated O2(-):H2O2 ratio as a prosurvival signal in glioma-propagating cells (GPCs). We hypothesize that depleting this ratio sensitizes GPCs to apoptotic triggers. RESULTS: We observed that an elevated O2(-):H2O2 ratio conferred enhanced resistance in GPCs, and depletion of this ratio by pharmacological and genetic methods sensitized cells to apoptotic triggers. We established the reactive oxygen species (ROS) Index as a quantitative measure of a normalized O2(-):H2O2 ratio and determined its utility in predicting chemosensitivity. Importantly, mice implanted with GPCs of a reduced ROS Index demonstrated extended survival. Analysis of tumor sections revealed effective targeting of complementarity determinant 133 (CD133)- and nestin-expressing neural precursors. Further, we established the Connectivity Map to interrogate a gene signature derived from a varied ROS Index for the patterns of association with individual patient gene expression in four clinical databases. We showed that patients with a reduced ROS Index demonstrate better survival. These data provide clinical evidence for the viability of our O2(-):H2O2-mediated chemosensitivity profiles. INNOVATION AND CONCLUSION: Gliomas are notoriously recurrent and highly infiltrative, and have been shown to arise from stem-like cells. We implicate an elevated O2(-):H2O2 ratio as a prosurvival signal in GPC self-renewal and proliferation. The ROS Index provides quantification of O2(-):H2O2-mediated chemosensitivity, an advancement in a previously qualitative field. Intriguingly, glioma patients with a reduced ROS Index correlate with longer survival and the Proneural molecular classification, a feature frequently associated with tumors of better prognosis. These data emphasize the feasibility of manipulating the O2(-):H2O2 ratio as a therapeutic strategy.
