Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis Journal Article
| Authors: | Niola, F.; Zhao, X.; Singh, D.; Sullivan, R.; Castano, A.; Verrico, A.; Zoppoli, P.; Friedmann-Morvinski, D.; Sulman, E.; Barrett, L.; Zhuang, Y.; Verma, I.; Benezra, R.; Aldape, K.; Iavarone, A.; Lasorella, A. |
| Article Title: | 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. |
| Keywords: | signal transduction; cancer survival; controlled study; human cell; gene deletion; nonhuman; cancer patient; glioma; animal cell; mouse; animal tissue; inhibitor of differentiation 1; embryo; animal experiment; animal model; tumor regression; cancer model; carcinogenesis; cancer inhibition; glioma cell; mesenchymal stem cell; gene inactivation; inhibitor of differentiation 2; cell adhesion; stem cell niche; rap1 protein; inhibitor of differentiation 3; tumor ablation; regulator gene; mesenchymal high grade glioma |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 123 |
| Issue: | 1 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2013-01-02 |
| Start Page: | 405 |
| End Page: | 417 |
| Language: | English |
| DOI: | 10.1172/jci63811 |
| PROVIDER: | scopus |
| PMCID: | PMC3537192 |
| PUBMED: | 23241957 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 March 2013" - "CODEN: JCINA" - "Source: Scopus" |
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