Self-Renewal Does Not Predict Tumor Growth Potential in Mouse Models of High-Grade Glioma

Barrett, Lindy E.; Granot, Zvi; Coker, Courtney; Iavarone, Antonio; Hambardzumyan, Dolores; Holland, Eric C.; Nam, Hyung Song; Benezra, Robert

doi:10.1016/j.ccr.2011.11.025

Cited by 120 publications

(124 citation statements)

References 44 publications

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“…The biological roles and mechanisms of ID family proteins in glioblastoma have been the subject of intense recent investigation (23,(33)(34)(35)(36). Benezra and colleagues (23) identified a self-renewing subpopulation expressing high levels of Id1 in a PDGFB-driven Arf −/− mouse model of glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

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Section: Discussionmentioning

confidence: 99%

“…5A) (18,(23)(24)(25). Among these genes, E2F2 RNAi consistently decreased the levels of helixloop-helix gene inhibitor of differentiation 1 (ID1) (Fig.…”

Section: -L)mentioning

confidence: 99%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…16 Among the markers used for identification of TICs (some not applicable in a prospective manner) are Nestin, SOX2, ID1, CD15, CD44, Integrin alpha 6, and the ability to extrude Hoechst dye (known as side-population analysis). 4,7,38,56 In fact, part of the issue with identifying a reliable marker for TICs is that more than one type of TIC likely exists in glioblastoma, a concept most recently supported by the observation that TICs grown in sphere culture cluster predominantly into two transcriptomic subtypes-proneural and mesenchymal-with transcriptional parallels to the respective TCGA subtypes. 7 Importantly, compared with proneural TICs, mesenchymal TICs were relatively radioresistant, in a manner dependent on NF-kB activity.…”

Section: Identification Of a Subpopulation Of Tumor-initiating Cellsmentioning

confidence: 99%

Molecular and cellular heterogeneity: the hallmark of glioblastoma

Aum

Kim

Beaumont

et al. 2014

FOC

172

105

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There has been increasing awareness that glioblastoma, which may seem histopathologically similar across many tumors, actually represents a group of molecularly distinct tumors. Emerging evidence suggests that cells even within the same tumor exhibit wide-ranging molecular diversity. Parallel to the discoveries of molecular heterogeneity among tumors and their individual cells, intense investigation of the cellular biology of glioblastoma has revealed that not all cancer cells within a given tumor behave the same. The identification of a subpopulation of brain tumor cells termed “glioblastoma cancer stem cells” or “tumor-initiating cells” has implications for the management of glioblastoma. This focused review will therefore summarize emerging concepts on the molecular and cellular heterogeneity of glioblastoma and emphasize that we should begin to consider each individual glioblastoma to be an ensemble of molecularly distinct subclones that reflect a spectrum of dynamic cell states.

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“…Expression of ID1 and ID3 has been associated with the tumor-initiating capacity of GICs, and recent work has established that overexpression of ID proteins is sufficient to reprogram Ink4a/Arf -/-astrocytes to cells with GIC features (16)(17)(18). However, ablation of Id1 alone or in combination with Id3 has minimal effect on tumor growth and animal survival in mouse models of HGG displaying a proneural phenotype (19). High levels of ID1 identify glioma cells with high self-renewal capacity but lower tumorigenic ability relative to that of cells with low expression of ID1 possessing limited self-renewal capacity.…”

Section: Introductionmentioning

confidence: 99%

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

Niola¹,

Zhao²,

Singh³

et al. 2012

J. Clin. Invest.

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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.

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Self-Renewal Does Not Predict Tumor Growth Potential in Mouse Models of High-Grade Glioma

Cited by 120 publications

References 44 publications

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Molecular and cellular heterogeneity: the hallmark of glioblastoma

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

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Self-Renewal Does Not Predict Tumor Growth Potential in Mouse Models of High-Grade Glioma

Cited by 120 publications

References 44 publications

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Molecular and cellular heterogeneity: the hallmark of glioblastoma

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

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An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma