Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis
Francesco Niola, … , Antonio Iavarone, Anna Lasorella
Francesco Niola, … , Antonio Iavarone, Anna Lasorella
Published December 17, 2012
Citation Information: J Clin Invest. 2013;123(1):405-417. https://doi.org/10.1172/JCI63811.
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Research Article Oncology

Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis

Abstract

High-grade gliomas (HGGs) are incurable brain tumors that are characterized by the presence of glioma-initiating cells (GICs). GICs are essential to tumor aggressiveness and retain the capacity for self-renewal and multilineage differentiation as long as they reside in the perivascular niche. ID proteins are master regulators of stemness and anchorage to the extracellular niche microenvironment, suggesting that they may play a role in maintaining GICs. Here, we modeled the probable therapeutic impact of ID inactivation in HGG by selective ablation of Id in tumor cells and after tumor initiation in a new mouse model of human mesenchymal HGG. Deletion of 3 Id genes induced rapid release of GICs from the perivascular niche, followed by tumor regression. GIC displacement was mediated by derepression of Rap1gap and subsequent inhibition of RAP1, a master regulator of cell adhesion. We identified a signature module of 5 genes in the ID pathway, including RAP1GAP, which segregated 2 subgroups of glioma patients with markedly different clinical outcomes. The model-informed survival analysis together with genetic and functional studies establish that ID activity is required for the maintenance of mesenchymal HGG and suggest that pharmacological inactivation of ID proteins could serve as a therapeutic strategy.

Authors

Francesco Niola, Xudong Zhao, Devendra Singh, Ryan Sullivan, Angelica Castano, Antonio Verrico, Pietro Zoppoli, Dinorah Friedmann-Morvinski, Erik Sulman, Lindy Barrett, Yuan Zhuang, Inder Verma, Robert Benezra, Ken Aldape, Antonio Iavarone, Anna Lasorella

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Figure 1

HGG arising in mice injected with Ras-V12-IRES-Cre-ER-shp53 lentivirus.

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HGG arising in mice injected with Ras-V12-IRES-Cre-ER-shp53 lentivirus. ...
(A) H&E staining and immunophenotype of a representative tumor lesion in the hippocampi of Id-cTKO mice 12 days after stereotaxic injection with Ras-V12-IRES-Cre-ER-shp53 lentivirus. Adjacent sections were immunostained using the indicated antibodies. Scale bars: 500 μm. (B) Representative microphotographs of H&E staining of advanced Ras-V12-IRES-Cre-ER-shp53–generated tumors showing histological features of HGG. The arrow indicates a multinucleated glioblastoma giant cell. Arrowheads point at clusters of tumor cells infiltrating the normal brain. N, necrotic foci. Scale bars: 500 μm (top left panel); 100 μm (top right and bottom panels). (C) Immunofluorescence staining of representative brain sections from mice injected with Ras-V12-IRES-Cre-ER-shp53 lentivirus sacrificed after the manifestation of neurological symptoms. Glioma and stem cell markers (Nestin, Olig2, and GFAP), ID1, ID2, the proliferation marker Ki67, and vascular endothelial cell marker CD31 are widely expressed. βIII-Tubulin is present in scattered cells. The arrow indicates the soma of a neuron. Arrowheads point at clusters of tumor cells infiltrating the normal brain. Scale bars: 100 μm (Nestin, Olig2, βIII-tubulin, GFAP, and Ki67); 200 μm (ID1, ID2, and CD31). (D) Double immunofluorescence staining for ID1 (green) and ID2 (red) shows coexpression of ID1 and ID2 in the vast majority of tumors cells. Nuclei were counterstained with DAPI (blue). Arrowheads and arrows point to single-positive and double-positive cells, respectively. Scale bars: 20 μm.