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Fig. 5 | Acta Neuropathologica Communications

Fig. 5

From: Novel targetable FGFR2 and FGFR3 alterations in glioblastoma associate with aggressive phenotype and distinct gene expression programs

Fig. 5

Oncogenetic programs in FGFR glioblastoma. a Nodal evolution of the LG FGFR2-TACC2 IDH-mutant astrocytoma (green tracing) into HG core F2↑ and LM F2T2↑ components (red tracing). Nodes are indicated with blue circles. Res1/Res2, first/second resections. The axial T2W-FLAIR MRI shows the outlined tumor components and the approximate 2D projection of the samples (circles). b Morphogenetic programs in FGFR glioblastoma with cartoon representation of specific morphologic features: HG neuroendocrine (NE)/embryonal, showing nuclear molding and high nuclear-cytoplasmic ratio; rhabdoid, showing eccentric nuclei and paranuclear vimentin whorls; FGFR3-TACC3 recurrent morphological features, showing cells with monomorphous nuclei aligned along chicken-wire capillaries. c Cartoon representation of the ECM remodeling fibrin cluster strongly upregulated in F2T2↑ and FGFR3 tumors. Red arrows indicate proteolytic cleavage. The end-product of the pathway, plasmin, activated by both uPA and tPA and membrane-bound via the heterotetrameric receptor complex formed by annexin A2/ANXA2 and p11/S100A10, activates uPA, growth factors (GFs), MMPs and other ECM components beside degrading fibrin. d Negative feedback loops regulating canonical pathway signaling are represented with thick or thin purple lines when the mechanism is known or only putative, respectively. FGFs bind to transmembrane amplified FGFR2 (F2↑ tumor) that activates (red arrows) canonic PI3K and ERK pathways but also PLCγ through a C-terminal Y-motif. FGF1-2 feedback inhibition may stem from DACH1, a transcriptional repressor downstream of FGFR signaling. In FGFR-fused tumors with moieties promoting mislocalization and constitutive FGFR dimerization and activation, only the PI3K and ERK canonic pathways are activated. Strong ERK activation leads to transcription of multiple pathway inhibitors, with corresponding expression levels shown for F2T2↑ and FGFR3-fused tumors

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