Abstract
Glioblastomas (GBMs) are incurable brain tumors with a high degree of cellular heterogeneity and genetic mutations. Transcription factors that normally regulate neural progenitors and glial development are aberrantly coexpressed in GBM, conferring cancer stem‐like properties to drive tumor progression and therapeutic resistance. However, the functional role of individual transcription factors in GBMs in vivo remains elusive. Here, we demonstrate that the basic‐helix–loop–helix transcription factor ASCL1 regulates transcriptional targets that are central to GBM development, including neural stem cell and glial transcription factors, oncogenic signaling molecules, chromatin modifying genes, and cell cycle and mitotic genes. We also show that the loss of ASCL1 significantly reduces the proliferation of GBMs induced in the brain of a genetically relevant glioma mouse model, resulting in extended survival times. RNA‐seq analysis of mouse GBM tumors reveal that the loss of ASCL1 is associated with downregulation of cell cycle genes, illustrating an important role for ASCL1 in controlling the proliferation of GBM.
Highlights
Glioblastomas (GBMs) are incurable brain tumors most commonly found in adults
Colocalization analysis revealed that 48% of ASCL1+ tumor cells were positive for the proliferation marker Ki67 (Figure 1k–m,o), whereas over 90% of ASCL1+ cells were OLIG2+ and SOX2+ (Figure 1o), indicating that these three transcription factors are coexpressed in the majority of the patient-derived xenograft (PDX)-GBM cells in vivo
When mice carrying a GlastCreERT2/+ knock-in allele (Mori et al, 2006) was crossed with the Rosa26-loxP-stop-loxP-tdTomato (R26RLSL-tdTom) reporter line (Madisen et al, 2010), we found that tdTomato fluorescence was restricted in the brain of neonatal pups if tamoxifen was administered at E14.5 (Figure 3a–c), making GlastCreERT2/+ ideal to combine with the Nf1F/F;Tp53F/F alleles to induce brain tumors
Summary
Glioblastomas (GBMs) are incurable brain tumors most commonly found in adults. Despite significant advances in imaging and surgical resection techniques combined with aggressive radiotherapy and chemotherapy, the median survival for GBM patients remains stagnated between 14 and 16 months, with greater than 90% of patients succumbing to their disease within 5 years of diagnosis (Ostrom et al, 2016). Despite displaying an aberrant array of mutations, GSCs are universally marked by coexpression of a combination of transcription factors, some of which include ASCL1, NFIA, NKX2.2, OLIG2, POU3F2, SALL2, SOX2, and ZEB1 (Glasgow et al, 2017; Lu et al, 2016; Rheinbay et al, 2013; Singh et al, 2017; Suva et al, 2014). These transcription factors have been extensively studied in the developing central nervous system (CNS), where each has been shown to regulate the fate, proliferation and/or migration of neural progenitor and glial precursor cells in stage specific processes. We sought to identify the direct in vivo role and transcriptional targets of ASCL1 in brain tumors of previously characterized patient-derived xenograft (PDX)-GBM (Marian et al, 2010; Marin-Valencia et al, 2012) and a genetically engineered glioma mouse model (Lin et al, 2004; Zhu et al, 2001)
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