A STAT3-based gene signature stratifies glioma patients for targeted therapy.
Melanie Si Yan TanEdwin SandanarajYuk Kien ChongSee Wee LimLynnette Wei Hsien KohWai Hoe NgNguan Soon TanPatrick TanBeng Ti AngCarol TangPublished in: Nature communications (2019)
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.
Keyphrases
- cell proliferation
- induced apoptosis
- end stage renal disease
- stem cells
- chronic kidney disease
- newly diagnosed
- type diabetes
- transcription factor
- bone marrow
- genome wide
- adipose tissue
- cell death
- gene expression
- metabolic syndrome
- oxidative stress
- peritoneal dialysis
- smoking cessation
- genome wide identification
- signaling pathway