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Cell Death Differ. 2019 Sep;26(9):1813-1831. doi: 10.1038/s41418-018-0248-7. Epub 2018 Dec 11.

The proneural gene ASCL1 governs the transcriptional subgroup affiliation in glioblastoma stem cells by directly repressing the mesenchymal gene NDRG1.

Author information

1
Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.
2
Department of Neurosurgery and Gamma Knife Radiosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
3
Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, 25124, Brescia, Italy.
4
Istituto Nazionale di Genetica Molecolare (INGM), Via Francesco Sforza 35, 20122, Milan, Italy.
5
CRS4, Biomedicine, Scientific Park of Sardinia, Pula, Cagliari, Italy.
6
Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
7
Neuroradiology Unit and CERMAC, Vita-Salute San Raffaele University and San Raffaele Scientific Institute, 20132, Milan, Italy.
8
Center for Research and Drug Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
9
Institut Univérsitaire d'Hématologie, Hôpital Saint-Louis, 75010, Paris, France.
10
Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. galli.rossella@hsr.it.

Abstract

Achaete-scute homolog 1 gene (ASCL1) is a gene classifier for the proneural (PN) transcriptional subgroup of glioblastoma (GBM) that has a relevant role in the neuronal-like differentiation of GBM cancer stem cells (CSCs) through the activation of a PN gene signature. Besides prototypical ASCL1 PN target genes, the molecular effectors mediating ASCL1 function in regulating GBM differentiation and, most relevantly, subgroup specification are currently unknown. Here we report that ASCL1 not only promotes the acquisition of a PN phenotype in CSCs by inducing a glial-to-neuronal lineage switch but also concomitantly represses mesenchymal (MES) features by directly downregulating the expression of N-Myc downstream-regulated gene 1 (NDRG1), which we propose as a novel gene classifier of MES GBMs. Increasing the expression of ASCL1 in PN CSCs results in suppression of self-renewal, promotion of differentiation and, most significantly, decrease in tumorigenesis, which is also reproduced by NDRG1 silencing. Conversely, both abrogation of ASCL1 expression in PN CSCs and enforcement of NDRG1 expression in either PN or MES CSCs induce proneural-to-mesenchymal transition (PMT) and enhanced mesenchymal features. Surprisingly, ASCL1 overexpression in MES CSCs increases malignant features and gives rise to a neuroendocrine-like secretory phenotype. Altogether, our results propose that the fine interplay between ASCL1 and its target NDRG1 might serve as potential subgroup-specific targetable vulnerability in GBM; enhancing ASCL1 expression in PN GBMs might reduce tumorigenesis, whereas repressing NDRG1 expression might be actionable to hamper the malignancy of GBM belonging to the MES subgroup.

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