P53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation

By Hongwu Zheng, Haoqiang Ying, Hai-yan Yan, Alec C. Kimmelman, David Hiller, An-Jou Chen, Samuel R. Perry, G. Tonon, Gerald C. Chu, Z. Ding and 10 more. Nature, 2008

744 citations recorded by the source corpus.

Glioblastoma (GBM) is a highly lethal brain tumour presenting as one of two subtypes with distinct clinical histories and molecular profiles. The primary GBM subtype presents acutely as a high-grade disease that typically harbours mutations in EGFR, PTEN and INK4A/ARF (also known as CDKN2A), and the secondary GBM subtype evolves from the slow progression of a low-grade disease that classically possesses PDGF and TP53 events. Here we show that concomitant central nervous system (CNS)-specific deletion of p53 and Pten in the mouse CNS generates a penetrant acute-onset high-grade malignant glioma phenotype with notable clinical, pathological and molecular resemblance to primary GBM in humans. This genetic observation prompted TP53 and PTEN mutational analysis in human primary GBM, demonstrating unexpectedly frequent inactivating mutations of TP53 as well as the expected PTEN mutations. Integrated transcriptomic profiling, in silico promoter analysis and functional studies of murine neural stem cells (NSCs) established that dual, but not singular, inactivation of p53 and Pten promotes an undifferentiated state with high renewal potential and drives increased Myc protein levels and its associated signature. Functional studies validated increased Myc activity as a potent contributor to the impaired differentiation and enhanced renewal of NSCs doubly null for p53 and Pten (p53-/- Pten-/-) as well as tumour neurospheres (TNSs) derived from this model. Myc also serves to maintain robust tumorigenic potential of p53-/- Pten-/- TNSs. These murine modelling studies, together with confirmatory transcriptomic/promoter studies in human primary GBM, validate a pathogenetic role of a common tumour suppressor mutation profile in human primary GBM and establish Myc as an important target for cooperative actions of p53 and Pten in the regulation of normal and malignant stem/progenitor cell differentiation, self-renewal and tumorigenic potential.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/679d742a5d06ce30c501637a491ba12a0e8eb191

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Citations in the corpus

MYC-induced Cancer Cell Energy Metabolism and Therapeutic Opportunities (2009, background): “Given the central role of MYC in many human cancers, it is critical that the c-Myc (herein termed Myc) transcription factor be well-understood, particularly regarding its role in stem cell maintenance and tumorigenesis (4-6).”
Targeting p53 pathways: mechanisms, structures and advances in therapy (2023, background): “148,149 Activation of p53 in breast, 150 prostate, 151 epidermis, 152 central nervous system 153 and hematopoietic stem cells 154 – 156 hinders stem cell self-renewal, but the exact mechanism remains to be con ﬁ rmed.”
PTEN loss in the continuum of common cancers, rare syndromes and mouse models (2011, positive): “Heterozygous deletion of Pten also accelerated glioblastoma formation that is induced by brain-specific heterozygous or homozygous deletion of Trp53 (Ref”
Lake-front property: a unique germinal niche by the lateral ventricles of the adult brain. (2011, positive): “In fact recent work suggests that deregulation of proliferation or oncogenic mutations within progenitor populations of the VZ-SVZ could lead to brain tumor formation (Persson et al., 2002; Zhu et al., 2005; Zheng et al., 2008; Alcantara Llaguno et al., 2009; Jacques et al., 2009)”
Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues (2019, background): “This example of abnormal lipid catabolism is due to ineffective degradation by the tumor suppressor phosphatase and tensin homolog (PTEN) [136,137].”
FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis (2009, methodology): “…a particular hGFAP-Cre transgenic line that has been well documented in multiple published studies to be highly active in neural stem/ progenitor cells (Figures S1G and S1H; Zheng et al., 2008; Zhuo et al., 2001; Lim et al., 2009) although it is also active in developing and mature astrocytes.”
Cancer stem cells in glioblastoma (2015, background): “CSC regulation converges on MYC, which occurs in the presence of MYC-mediated cancer cell survival and proliferation programs (Wang et al. 2008; Zheng et al. 2008; Wurdak et al. 2010; Chan et al. 2012; Fang et al. 2014).”
Integrin alpha 6 regulates glioblastoma stem cells (2010, background): “Although the exact pathway to which integrin a6 is driving the GSC phenotype is yet to be determined, it is likely to involve common downstream molecules of integrins such as Akt and c-myc, which we and others recently showed were also critical in GSC maintenance (Eyler et al., 2008; Wang et al., 20”