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.
Highlights
Predicting clinical course and delivering therapeutics based on the genetic makeup of tumors is of utmost significance to increase efficacy and prevent overtreatment in patients
Achaete-scute homolog 1 gene (ASCL1) expression in a subset of GBM cancer stem cells (CSCs) activates neuronal target genes and promotes responsiveness to Notch inhibitors, resulting in impaired tumorigenicity [20]. We extend the latter findings by reporting that ASCL1 regulates the phenotypic switch between GBM subgroups by directly repressing the expression of N-Myc downstream-regulated gene 1 (NDRG1) that we functionally identified as a novel MES subgroup gene classifier
We asked whether subgroup-specific gene classifiers could be pinpointed and endorsed as subsidiary diagnostic/prognostic markers and potentially actionable vulnerabilities for GBM, as documented for subgroup-restricted molecular mediators, such as STAT3, CEBPB/D, TAZ, Olig2, MLK4, and DGKα [32] [33, 15, 14, 34]
Summary
Predicting clinical course and delivering therapeutics based on the genetic makeup of tumors is of utmost significance to increase efficacy and prevent overtreatment in patients. This notion applies to glioblastoma (GBM), which is the most malignant brain tumor of adults and accounts for 50% of the newly diagnosed glioma [1]. The PN signature correlates with a slightly less aggressive disease and increased response to anti-angiogenic treatment in patients with IDH-wild-type GBM, whereas the MES subgroup has been associated with radio-resistance and poorer prognosis [6, 7]
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