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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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 2

Ablation of Id in cancer cells affects tumor maintenance in Ras-V12-IRES-Cre-ER-shp53 HGG.

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Ablation of Id in cancer cells affects tumor maintenance in Ras-V12-IRES...
(A) Kaplan-Meier survival curves of Id-cTKO mice injected intracranially with Ras-V12-IRES-Cre-ER-shp53 lentivirus that had received systemic tamoxifen or oil. Points on the curves indicate deaths (n = 13 for oil and n = 11 for tamoxifen). P = 0.002. (B) H&E staining and immunophenotype on adjacent sections of representative brains from Id-cTKO mice treated with tamoxifen or oil and sacrificed 6 weeks after stereotaxic injection with Ras-V12-IRES-Cre-ER-shp53 lentivirus. The boxed tumor is shown at higher magnification in the inset. Arrowheads indicate injection track. T, tumor. Scale bars: 500 μm (H&E, ID1, Ki67, and Nestin); 20 μm (SSEA1). Original magnification, ×10 (inset). (C) Quantification of tumor volume in mice as in B (n = 3 per each treatment group). *P = 0.0381. (D) Quantification of Ki67+ cells in tumors as in B. (n = 3 per each treatment group). *P = 0.0024. (E). Quantification of SSEA1+ cells in tumors as in B (n = 3 per each treatment group). *P = 0.0002. Data are mean ± SD.