2 research outputs found
Integrative clinical transcriptome analysis reveals TMPRSS2āERG dependency of prognostic biomarkers in prostate adenocarcinoma
In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2āERG (T2E)āfusion oncoproteins defining two molecular subtypes (T2Eāpositive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate geneāsignatures associated with metastasis in T2Eāpositive and T2Eānegative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasisāassociated geneāsignatures regarding the T2Eāstatus. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2Eāstatus. Using geneāset enrichment analyses, we uncovered that metastatic T2Eāpositive and T2Eānegative PCa are characterized by distinct geneāsignatures. In addition, by testing genes shared by several functional geneāsignatures for their association with eventāfree survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)āthree of which are included in commercially available prognostic testsāwhose high expression was significantly associated with worse outcome exclusively in T2Eānegative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2Eānegative patients. No prognostic biomarkers were identified exclusively for T2Eāpositive tumors. Collectively, our study discovers that the T2Eāstatus, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa
Oncogenic hijacking of a developmental transcription factor evokes vulnerability toward oxidative stress in Ewing sarcoma
Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal
stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins
involving EWSR1 and variable members of the ETS-family of transcription factors (in 85%
FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites as enhancers.
Here, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 ā a
physiological driver of proliferation of osteo-chondrogenic progenitors ā by binding to an
intronic GGAA-microsatellite, which promotes EwS growth in vitro and in vivo. Through
integration of transcriptome-profiling, published drug-screening data, and functional in vitro
and in vivo experiments including 3D and PDX models, we discover that constitutively high
SOX6 expression promotes elevated levels of oxidative stress that create a therapeutic
vulnerability toward the oxidative stress-inducing drug Elesclomol.
Collectively, our results exemplify how aberrant activation of a developmental transcription
factor by a dominant oncogene can promote malignancy, but provide opportunities for tar-
geted therapy