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 8

Loss of cell adhesion by Rap1GAP in GICs is independent of proliferation.

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Loss of cell adhesion by Rap1GAP in GICs is independent of proliferation...
(A) Western blot analysis for Rap1GAP and p27Kip1 expression in GICs transduced with pLOC-Rap1GAP-GFP, pLOC-p27Kip1-GFP, or pLOC-GFP. β-Actin is shown as loading control. (B) Microphotographs of human GICs transduced with pLOC-Rap1GAP-GFP, pLOC-p27KIP1-GFP, or pLOC-GFP and assayed for adhesion to endothelial cells. Scale bars: 100 μm. (C) The number of adherent GFP+ cells was determined by high-power microscopy review. Data represent the mean ± SD of triplicate samples from 2 independent experiments. *P = 2.4069 × 10–5. (D) The number of tumor spheres obtained from human GICs treated as in B and seeded at <1 cell per μl was determined by microscopy review. Data represent the mean ± SD of triplicate samples. *P = 5.05863 × 10–5.