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.
authors.affiliation: Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Niola
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhao
authors.forename: Devendra
authors.initials: D
authors.lastname: Singh
authors.forename: Ryan
authors.initials: R
authors.lastname: Sullivan
authors.forename: Angelica
authors.initials: A
authors.lastname: Castano
authors.forename: Antonio
authors.initials: A
authors.lastname: Verrico
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.forename: Dinorah
authors.initials: D
authors.lastname: Friedmann-Morvinski
authors.forename: Erik
authors.initials: E
authors.lastname: Sulman
authors.forename: Lindy
authors.initials: L
authors.lastname: Barrett
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Inder
authors.initials: I
authors.lastname: Verma
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
authors.forename: Ken
authors.initials: K
authors.lastname: Aldape
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D057809:HEK293 Cells; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000089804:Shelterin Complex; D015996:Survival Rate; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D009363:Neoplasm Proteins; C484658:RAP1GAP protein, human; C539504:Rap1GAP protein, mouse; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins