Abstract
Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.
Highlights
Glioblastomas (GBMs) are tumors of the central nervous system that are among the deadliest cancers
GBMs were one of the first tumor types to be comprehensively explored by next-generation sequencing, leading to the identification of frequent genomic alterations and the development of molecular classification methods [2,3,4]
A classification based on gene expression profiles identified four molecular subtypes (Proneural, Neural, Mesenchymal, and Classical) [3]
Summary
Glioblastomas (GBMs) are tumors of the central nervous system that are among the deadliest cancers. Gene expression at the mRNA level revealed populations of cells representing all of the different GBM subgroups and supported the conclusion that these tumors comprehend a heterogeneous mixture of cells [18] These studies present the idea that tumor heterogeneity is a possible asset to evade therapy and generate resistance, since the presence of many populations of tumor cells bearing different molecular characteristics will result in drug sensitivity heterogeneity [21,22]. Studies show that low-grade gliomas and their paired recurrences display high molecular divergence [17] To address these issues, we evaluated a specific transcriptomic and translatomic signature of the GBM heterogeneity at the single-patient level. Our results demonstrate for the first time that the isolation of mRNA engaged in translation can be used to identify biomarkers of tumor progression and reveal previously unappreciated heterogeneity in diverse regulatory programs central to GBM biology, prognosis, and therapy
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