Mesenchymal and Proneural Subtypes of Glioblastoma Disclose Branching Based on GSC Associated Signature

Abstract

Glioblastomas (GBM)—the most common, therapy-resistant, and lethal tumors driven by populations of glioma stem cells (GSCs) are still on the list of the most complicated pathologies. Thus, deeper understanding and characterization of GSCs is indispensable to find suitable targets and develop more effective therapies. In the present study, we applied native glioblastoma cells and GSCs sequencing, screened for GSC-specific targets and checked if the signature is related to GBM patient pathological, clinical data as well as molecular subtypes applying TCGA cohort. Data analysis revealed that tumors of proneural and mesenchymal subtypes are branching in separate clusters based on screened gene expression. Samples of the same subtype revealed significantly different patient survival prognosis as well as recurrence chance between the clusters. Recently, different subpopulations of mesenchymal GSC demonstrating different properties were shown, which indicates possible internal heterogeneity of GBM subtypes as well. Current findings also revealed branching of molecular GBM subtypes that were significantly linked to patient outcome and that might be decided by distinct GSC subpopulations.

ERK Phosphorylation Regulates the Aml1/Runx1 Splice Variants and the TRP Channels Expression during the Differentiation of Glioma Stem Cell Lines

“…Moreover, increased levels of immunoglobulin kappa J region (RBPJ) mRNA, which contributes to GBM malignancy and promotes proneural-mesenchymal transition via the IL-6/STA3 pathway [77], were evidenced in MES-like GSC#83 cells, suggesting that mesenchymal GSC#83 may be derived from a GSC with a proneural phenotype [15]. In the GBM stem cell compartment, the proneural-mesenchymal transition, the equivalent of the epithelial-mesenchymal transition associated with aggressive cancers, under the selective pressure of treatment agents is responsible for the acquisition of multitherapy resistance phenotype [78].…”

“…Herein, the expression of Aml1b and Aml1c splice variants was analyzed at mRNA level by qRT-PCR in seven different GSC lines, with PN-(GSC#1, #23C, #28, #68 and #70), and MES-like phenotype (GSC#30 and GSC#83) [14,15,32]. An Aml1b and Aml1c mRNA upregulation, although at different levels, was observed in all the GSCs analyzed, compared with NSCs.…”

“…Previous studies unveiled the interand intra-tumor heterogeneity of GSCs. At transcription levels, at least two mutually distinct subtypes of GSCs, a proneural-like (PN-like) and a mesenchymal-like (MES-like) phenotype, were identified [14,15]. MES-like GSCs showed higher rates of proliferation in vitro and in vivo; they are more angiogenic, invasive and resistant to radiation than PN-like GSCs [16].…”

“…MES-like GSCs showed higher rates of proliferation in vitro and in vivo; they are more angiogenic, invasive and resistant to radiation than PN-like GSCs [16]. Moreover, it was found that primary treated PN-like GBM often relapse, as tumors having MES-like markers become resistant to therapy [15,17].…”

Multiple Antitumor Molecular Mechanisms Are Activated by a Fully Synthetic and Stabilized Pharmaceutical Product Delivering the Active Compound Sulforaphane (SFX-01) in Preclinical Model of Human Glioblastoma

“…Genetically, the tumor heterogeneity of GBM is represented by four clinically relevant subtypes [11]: proneural (PN), neural (NL), classical (CL), and mesenchymal (Mes) also if extreme heterogeneity exists even within each subgroup. This classification has strong implications in the selection of anti-target therapies [12]. The MES subtype represents the most aggressive phenotype, which is strongly associated with poor prognosis, compared with the PN subtype.…”