Cellular and molecular characterization of IDH1‐mutated diffuse low grade gliomas reveals tumor heterogeneity and absence of EGFR/PDGFRα activation

Abstract

Diffuse low grade gliomas (DLGG, grade II gliomas) are slowly-growing brain tumors that often progress into high grade gliomas. Most tumors have a missense mutation for IDH1 combined with 1p19q codeletion in oligodendrogliomas or ATRX/TP53 mutations in astrocytomas. The phenotype of tumoral cells, their environment and the pathways activated in these tumors are still ill-defined and are mainly based on genomics and transcriptomics analysis. Here we used freshly-resected tumors to accurately characterize the tumoral cell population and their environment. In oligodendrogliomas, cells express the transcription factors MYT1, Nkx2.2, Olig1, Olig2, Sox8, four receptors (EGFR, PDGFRα, LIFR, PTPRZ1) but not the co-receptor NG2 known to be expressed by oligodendrocyte progenitor cells. A variable fraction of cells also express the more mature oligodendrocytic markers NOGO-A and MAG. DLGG cells are also stained for the young-neuron marker doublecortin (Dcx) which is also observed in oligodendrocytic cells in nontumoral human brain. In astrocytomas, MYT1, PDGFRα, PTPRZ1 were less expressed whereas Sox9 was prominent over Sox8. The phenotype of DLGG cells is overall maintained in culture. Phospho-array screening showed the absence of EGFR and PDGFRα phosphorylation in DLGG but revealed the strong activation of p44/42 MAPK/ERK which was present in a fraction of tumoral cells but also in nontumoral cells. These results provide evidence for the existence of close relationships between the cellular phenotype and the mutations found in DLGG. The slow proliferation of these tumors may be associated with the absence of activation of PDGFRα/EGFR receptors.

Characterization of iPSCs derived from low grade gliomas revealed early regional chromosomal amplifications during gliomagenesis

“…5B), suggesting that these amplifications are recurrent events and functionally important to LGGs. Consistent with this notion, several recent studies implicated potential roles of the genes within the amplified regions, such as FEZF1 [44], PTPRZ1 [45,46], AASS and TAS2R16 [47], in gliomagenesis (Table 1). Therefore, more research would be necessary to fully appreciate the functional consequence of these regional chromosomal amplifications in gliomagenesis.…”

Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL, a Negative Regulator of Glioma Growth

“…For EdU incorporation, cells were incubated with EdU 10 μM for 4 hours and processed for staining following manufacturer's recommendation (Baseclick kit). Explant cultures of IDH1-mutated diffuse low-grade gliomas used to explore the expression of ETNPPL are described in 12 .…”

“…Western blots. Total proteins from tissue samples and cultured cells were obtained and used for Western Blot as described by 12 . Proteins were detected using the Odyssey CLx Li-Cor technology.…”

CeRNA Network Analysis Representing Characteristics of Different Tumor Environments Based on 1p/19q Codeletion in Oligodendrogliomas

“…IDH1 and IDH2 (collectively referred to as IDH hereafter), which encode isocitrate dehydrogenase and cause mutations and 1p/19q codeletion, were included as characteristic prognostic markers of ODs [5]. Although the 1p/19q codeletion is a prognostic marker of ODs with IDH1/2 mutations [6,7], 30-40% of all ODs are not codeleted at 1p/19q and have a worse prognosis [8][9][10]. Hence, the 1p/19q codeletion is reportedly associated with diagnosis, prognosis, and clinically favorable overall survival (OS) in glioma; however, the exact underlying mechanism remains unclear [3,[11][12][13][14][15][16].…”