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A glial blueprint for gliomagenesis

Nature Reviews Neuroscience volume 19, pages 393–403 (2018)Cite this article

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Abstract

Gliomas are heterogeneous tumours derived from glial cells and remain the deadliest form of brain cancer. Although the glioma stem cell sits at the apex of the cellular hierarchy, how it produces the vast cellular constituency associated with frank glioma remains poorly defined. We explore glioma tumorigenesis through the lens of glial development, starting with the neurogenic–gliogenic switch and progressing through oligodendrocyte and astrocyte differentiation. Beginning with the factors that influence normal glial linage progression and diversity, a pattern emerges that has useful parallels in the development of glioma and may ultimately provide targetable pathways for much-needed new therapeutics.

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Fig. 1: Overview of glioma subtypes.
Fig. 2: The gliogenic switch and glioma.
Fig. 3: Glial developmental factors influence tumour identity.
Fig. 4: Astrocyte and oligodendrocyte lineage trajectories.

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References

  1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). This review is the expanded version of the canonical primer on cancer biology.

    Article  PubMed  CAS  Google Scholar 

  2. Wainwright, E. N. & Scaffidi, P. Epigenetics and cancer stem cells: unleashing, hijacking, and restricting cellular plasticity. Trends Cancer 3, 372–386 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Takebe, N. et al. Targeting notch, hedgehog, and wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015). This is a comprehensive review of the current pipeline therapies targeting developmental pathway components for glioma treatment.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Joruiz, S. M. & Bourdon, J. C. p53 isoforms: key regulators of the cell fate decision. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a026039 (2016).

  5. Veleva-Rotse, B. O. & Barnes, A. P. Brain patterning perturbations following PTEN loss. Front. Mol. Neurosci. 7, 35 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Molofsky, A. V. et al. Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sanchez-Martin, M. & Ferrando, A. The NOTCH1-MYC highway toward T cell acute lymphoblastic leukemia. Blood 129, 1124–1133 (2017).

    Article  PubMed  CAS  Google Scholar 

  8. Mok, T. S. Personalized medicine in lung cancer: what we need to know. Nat. Rev. Clin. Oncol. 8, 661–668 (2011).

    Article  PubMed  CAS  Google Scholar 

  9. Birey, F., Kokkosis, A. G. & Aguirre, A. Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders. Curr. Opin. Neurobiol. 47, 93–103 (2017).

    Article  PubMed  CAS  Google Scholar 

  10. Molofsky, A. V. & Deneen, B. Astrocyte development: a guide for the perplexed. Glia 63, 1320–1329 (2015). This review provides a thorough and approachable description of astrocyte development.

    Article  PubMed  Google Scholar 

  11. Louis, D. N. et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  PubMed  Google Scholar 

  12. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013). This study presents a characterization of adult GBM subtypes on the basis of relevant patterns of somatic mutations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Baker, S. J., Ellison, D. W. & Gutmann, D. H. Pediatric gliomas as neurodevelopmental disorders. Glia 64, 879–895 (2016). This article presents a thorough discussion of the unique properties of paediatric gliomas, how they differ from adult gliomas and the genetic basis for their relationship to development.

    PubMed  Google Scholar 

  15. Jones, C. & Baker, S. J. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat. Rev. Cancer https://doi.org/10.1038/nrc3811 (2014).

  16. Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537 e525 (2017). This paper provides a thorough and modern classification of paediatric glioma subtypes on the basis of patient genomic alterations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    Article  PubMed  CAS  Google Scholar 

  18. Wu, S., Wu, Y. & Capecchi, M. R. Motoneurons and oligodendrocytes are sequentially generated from neural stem cells but do not appear to share common lineage-restricted progenitors in vivo. Development 133, 581–590 (2006).

    Article  PubMed  CAS  Google Scholar 

  19. Masahira, N. et al. Olig2-positive progenitors in the embryonic spinal cord give rise not only to motoneurons and oligodendrocytes, but also to a subset of astrocytes and ependymal cells. Dev. Biol. 293, 358–369 (2006).

    Article  PubMed  CAS  Google Scholar 

  20. Ravanelli, A. M. & Appel, B. Motor neurons and oligodendrocytes arise from distinct cell lineages by progenitor recruitment. Genes Dev. 29, 2504–2515 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Mukouyama, Y. S. et al. Olig2+ neuroepithelial motoneuron progenitors are not multipotent stem cells in vivo. Proc. Natl Acad. Sci. USA 103, 1551–1556 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Stolt, C. C. et al. The Sox9 transcription factor determines glial fate choice in the developing spinal cord. Genes Dev. 17, 1677–1689 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Deneen, B. et al. The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord. Neuron 52, 953–968 (2006).

    Article  PubMed  CAS  Google Scholar 

  24. Kang, P. et al. Sox9 and NFIA coordinate a transcriptional regulatory cascade during the initiation of gliogenesis. Neuron 74, 79–94 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Glasgow, S. M. et al. Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis. Nat. Neurosci. 20, 1520–1528 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Hatakeyama, J. et al. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 131, 5539–5550 (2004).

    Article  PubMed  CAS  Google Scholar 

  27. Park, H. C. & Appel, B. Delta-Notch signaling regulates oligodendrocyte specification. Development 130, 3747–3755 (2003).

    Article  PubMed  CAS  Google Scholar 

  28. Taylor, M. K., Yeager, K. & Morrison, S. J. Physiological notch signaling promotes gliogenesis in the developing peripheral and central nervous systems. Development 134, 2435–2447 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Namihira, M. et al. Committed neuronal precursors confer astrocytic potential on residual neural precursor cells. Dev. Cell 16, 245–255 (2009).

    Article  PubMed  CAS  Google Scholar 

  30. Suva, M. L. et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157, 580–594 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lan, X. et al. Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature 549, 227–232 (2017). This study elegantly shows that intratumoural GBM heterogeneity arises from hierarchical fate progression of GSCs, similar to that of developmental GSCs.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Glasgow, S. M. et al. The miR-223/nuclear factor I-A axis regulates glial precursor proliferation and tumorigenesis in the CNS. J. Neurosci. 33, 13560–13568 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Song, H. R. et al. Nuclear factor IA is expressed in astrocytomas and is associated with improved survival. Neuro Oncol. 12, 122–132 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Glasgow, S. M. et al. Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat. Neurosci. 17, 1322–1329 (2014). This paper draws parallels between glial development and glioma tumorigenesis through misexpression of glial-specific transcription factors SOX10 and NFIA.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Schlierf, B. et al. Expression of SoxE and SoxD genes in human gliomas. Neuropathol. Appl. Neurobiol. 33, 621–630 (2007).

    Article  PubMed  CAS  Google Scholar 

  36. Liu, H. et al. SOX9 overexpression promotes glioma metastasis via wnt/beta-catenin signaling. Cell Biochem. Biophys. 73, 205–212 (2015).

    Article  PubMed  CAS  Google Scholar 

  37. Swartling, F. J. et al. Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC. Cancer Cell 21, 601–613 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Teodorczyk, M. & Schmidt, M. H. Notching on cancer’s door: notch signaling in brain tumors. Front. Oncol. 4, 341 (2014).

    PubMed  Google Scholar 

  39. Giachino, C. et al. A tumor suppressor function for notch signaling in forebrain tumor subtypes. Cancer Cell 28, 730–742 (2015).

    Article  PubMed  CAS  Google Scholar 

  40. Xie, Q. et al. RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J. Clin. Invest. 126, 2757–2772 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liau, B. B. et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20, 233–246 e237 (2017). This paper highlights mechanisms through which GSCs reutilize developmental pathways and epigenetic programmes to transition between proliferative states and plasticity.

    Article  PubMed  CAS  Google Scholar 

  42. Fancy, S. P., Chan, J. R., Baranzini, S. E., Franklin, R. J. & Rowitch, D. H. Myelin regeneration: a recapitulation of development? Annu. Rev. Neurosci. 34, 21–43 (2011).

    Article  PubMed  CAS  Google Scholar 

  43. Emery, B. & Lu, Q. R. Transcriptional and epigenetic regulation of oligodendrocyte development and myelination in the central nervous system. Cold Spring Harb. Perspect. Biol. 7, a020461 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Bergles, D. E. & Richardson, W. D. Oligodendrocyte development and plasticity. Cold Spring Harb. Perspect. Biol. 8, a020453 (2015).

    Article  PubMed  CAS  Google Scholar 

  45. Dimou, L. & Gallo, V. NG2-glia and their functions in the central nervous system. Glia 63, 1429–1451 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Zhu, X. et al. Age-dependent fate and lineage restriction of single NG2 cells. Development 138, 745–753 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Nishiyama, A., Boshans, L., Goncalves, C. M., Wegrzyn, J. & Patel, K. D. Lineage, fate, and fate potential of NG2-glia. Brain Res. 1638, 116–128 (2016). This paper provides an extensive mapping of the potential and fate of NG2 cells, a proposed cell of origin for glioma.

    Article  PubMed  CAS  Google Scholar 

  48. Vigano, F. & Dimou, L. The heterogeneous nature of NG2-glia. Brain Res. 1638, 129–137 (2016).

    Article  PubMed  CAS  Google Scholar 

  49. Lu, Q. R. et al. Sonic hedgehog — regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25, 317–329 (2000).

    Article  PubMed  CAS  Google Scholar 

  50. Zhou, Q. & Anderson, D. J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  PubMed  CAS  Google Scholar 

  51. Britsch, S. et al. The transcription factor Sox10 is a key regulator of peripheral glial development. Genes Dev. 15, 66–78 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Finzsch, M., Stolt, C. C., Lommes, P. & Wegner, M. Sox9 and Sox10 influence survival and migration of oligodendrocyte precursors in the spinal cord by regulating PDGF receptor alpha expression. Development 135, 637–646 (2008).

    Article  PubMed  CAS  Google Scholar 

  53. Raff, M. C., Lillien, L. E., Richardson, W. D., Burne, J. F. & Noble, M. D. Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature 333, 562–565 (1988).

    Article  PubMed  CAS  Google Scholar 

  54. Fruttiger, M. et al. Defective oligodendrocyte development and severe hypomyelination in PDGF-A knockout mice. Development 126, 457–467 (1999).

    PubMed  CAS  Google Scholar 

  55. Chew, L. J., Coley, W., Cheng, Y. & Gallo, V. Mechanisms of regulation of oligodendrocyte development by p38 mitogen-activated protein kinase. J. Neurosci. 30, 11011–11027 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Holland, E. C. et al. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat. Genet. 25, 55–57 (2000).

    Article  PubMed  CAS  Google Scholar 

  57. Alcantara Llaguno, S. et al. Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 15, 45–56 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hambardzumyan, D., Parada, L. F., Holland, E. C. & Charest, A. Genetic modeling of gliomas in mice: new tools to tackle old problems. Glia 59, 1155–1168 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Alcantara Llaguno, S. R. et al. Adult lineage-restricted CNS progenitors specify distinct glioblastoma subtypes. Cancer Cell 28, 429–440 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Persson, A. I. et al. Non-stem cell origin for oligodendroglioma. Cancer Cell 18, 669–682 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Yadavilli, S. et al. The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma. Oncotarget 6, 12141–12155 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Ligon, K. L. et al. Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma. Neuron 53, 503–517 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ligon, K. L. et al. The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas. J. Neuropathol. Exp. Neurol. 63, 499–509 (2004).

    Article  PubMed  CAS  Google Scholar 

  65. Mehta, S. et al. The central nervous system-restricted transcription factor Olig2 opposes p53 responses to genotoxic damage in neural progenitors and malignant glioma. Cancer Cell 19, 359–371 (2011).

  66. Lu, F. et al. Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell 29, 669–683 (2016). This paper shows excellent use of genetic tools to modulate regulators of developmental gliogenesis during glioma tumorigenesis to affect glioma subtype identity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Zhou, J. et al. A sequentially priming phosphorylation cascade activates the gliomagenic transcription factor Olig2. Cell Rep. 18, 3167–3177 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Ferletta, M., Uhrbom, L., Olofsson, T., Ponten, F. & Westermark, B. Sox10 has a broad expression pattern in gliomas and enhances platelet-derived growth factor-B− -induced gliomagenesis. Mol. Cancer Res. 5, 891–897 (2007).

    Article  PubMed  CAS  Google Scholar 

  69. Heldin, C. H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun. Signal 11, 97 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Phillips, J. J. et al. PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol. 23, 565–573 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

    Article  CAS  Google Scholar 

  72. Dai, C. et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev. 15, 1913–1925 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Mellinghoff, I. K., Schultz, N., Mischel, P. S. & Cloughesy, T. F. Will kinase inhibitors make it as glioblastoma drugs? Curr. Top. Microbiol. Immunol. 355, 135–169 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  74. Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008). This paper describes a valuable database of transcriptome data from glial development that may be useful to inform glioma tumorigenesis studies.

    Article  PubMed  CAS  Google Scholar 

  75. Molofsky, A. V. et al. Expression profiling of Aldh1l1-precursors in the developing spinal cord reveals glial lineage-specific genes and direct Sox9-Nfe2l1 interactions. Glia 61, 1518–1532 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Chaboub, L. S. et al. Temporal profiling of astrocyte precursors reveals parallel roles for asef during development and after injury. J. Neurosci. 36, 11904–11917 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Tien, A. C. et al. Regulated temporal-spatial astrocyte precursor cell proliferation involves BRAF signalling in mammalian spinal cord. Development 139, 2477–2487 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ge, W. P., Miyawaki, A., Gage, F. H., Jan, Y. N. & Jan, L. Y. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376–380 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Jones, D. T. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat. Genet. 45, 927–932 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Tsai, H. H. et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337, 358–362 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Hochstim, C., Deneen, B., Lukaszewicz, A., Zhou, Q. & Anderson, D. J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133, 510–522 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549 e539 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Morel, L. et al. Molecular and functional properties of regional astrocytes in the adult brain. J. Neurosci. 37, 8706–8717 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Lin, J. C. C. et al. Identification of diverse astrocyte populations and their malignant analogs. Nat. Neurosci. 20, 396–405 (2017). This study found that molecularly distinct astrocyte populations isolated from healthy brain tissue have analogous populations in glioma tumours.

    Article  PubMed Central  CAS  Google Scholar 

  85. das Neves, L. et al. Disruption of the murine nuclear factor I-A gene (Nfia) results in perinatal lethality, hydrocephalus, and agenesis of the corpus callosum. Proc. Natl Acad. Sci. USA 96, 11946–11951 (1999).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Sun, W. et al. SOX9 is an astrocyte-specific nuclear marker in the adult brain outside the neurogenic regions. J. Neurosci. 37, 4493–4507 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 278, 477–483 (1997).

    Article  PubMed  CAS  Google Scholar 

  88. Barnabe-Heider, F. et al. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1. Neuron 48, 253–265 (2005).

    Article  PubMed  CAS  Google Scholar 

  89. Martini, S. et al. A critical role for Sox9 in notch-induced astrogliogenesis and stem cell maintenance. Stem Cells 31, 741–751 (2013).

    Article  PubMed  CAS  Google Scholar 

  90. Nagao, M., Ogata, T., Sawada, Y. & Gotoh, Y. Zbtb20 promotes astrocytogenesis during neocortical development. Nat. Commun. 7, 11102 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Magnusson, J. P. et al. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346, 237–241 (2014).

    Article  PubMed  CAS  Google Scholar 

  92. Darmanis, S. et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 21, 1399–1410 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. de la Iglesia, N., Puram, S. V. & Bonni, A. STAT3 regulation of glioblastoma pathogenesis. Curr. Mol. Med. 9, 580–590 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  95. de la Iglesia, N. et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev. 22, 449–462 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Fan, Q. W. et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 24, 438–449 (2013).

    Article  PubMed  CAS  Google Scholar 

  97. Jahani-Asl, A. et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat. Neurosci. 19, 798–806 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Jackson, C., Ruzevick, J., Amin, A. G. & Lim, M. Potential role for STAT3 inhibitors in glioblastoma. Neurosurg. Clin. N. Am. 23, 379–389 (2012).

    Article  PubMed  Google Scholar 

  99. Furtek, S. L., Backos, D. S., Matheson, C. J. & Reigan, P. Strategies and approaches of targeting STAT3 for cancer treatment. ACS Chem. Biol. 11, 308–318 (2016).

    Article  PubMed  CAS  Google Scholar 

  100. de The, H. Differentiation therapy revisited. Nat. Rev. Cancer 18, 117–127 (2018). This paper presents an interesting opinion on the ways that differentiation therapies have been used to treat certain tumours and how these treatments may be improved to treat other malignancies.

    Article  PubMed  CAS  Google Scholar 

  101. Ostrom, Q. T. et al. The epidemiology of glioma in adults: a “state of the science” review. Neuro Oncol. 16, 896–913 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors thank C. Gillespie for editing and reviewing this manuscript. This work was supported by grants from the US National Institutes of Health (NS071153 to B.D. and K01CA190235 and 5-T32HL092332-08 to S.M.G.) and the Cancer Prevention Research Institute of Texas (RP150334 and RP160192 to B.D.).

Reviewer information

Nature Reviews Neuroscience thanks B. Appel, W. Weiss, M. Monje and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    Dylan Laug, Stacey M. Glasgow & Benjamin Deneen

  2. Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA

    Dylan Laug & Benjamin Deneen

  3. Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Benjamin Deneen

  4. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Benjamin Deneen

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B.D. and D.L. researched data for the article and made a substantial contribution to the discussion of content and the writing, reviewing and editing of the manuscript before submission. S.M.G. researched data for the article.

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Correspondence to Benjamin Deneen.

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Glossary

Isocitrate dehydrogenase (IDH) status

Refers to whether a patient possesses a missense mutation in IDH1 or IDH2 that has been linked to glioma.

Frank glioma

A clinically diagnosed glioma.

Xenograft

A commonly used animal tumour model in which patient-derived cancer cells are transplanted under the skin or into the organ of interest in immune-deficient animals.

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Laug, D., Glasgow, S.M. & Deneen, B. A glial blueprint for gliomagenesis. Nat Rev Neurosci 19, 393–403 (2018). https://doi.org/10.1038/s41583-018-0014-3

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