ASCL1 regulates neurodevelopmental transcription factors and cell cycle genes in brain tumors of glioma mouse models

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.

Decoding Cortical Glial Cell Development

“…At the late embryonic stage, oscillation of Hes1 and an increase in SHH signaling in cortical RGCs result in upregulation of Ascl1 and Egfr in aMIPCs [ 13 , 36 , 55 , 64 , 65 ]. ASCL1 and EGFR may promote Olig2/1 expression [ 66 , 67 ]. Most important, an increase in SHH signaling strongly induces Olig2/1 expression [ 68 ].…”

The Role of Neurodevelopmental Pathways in Brain Tumors

“…Similarly, restoring ASCL1 expression to GSCs endogenously deficient in ASLC1 induces neuronal differentiation and reduces tumorigenesis by exposing the relevant chromatin regions for activation of neuronal lineage programs ( Park et al, 2017 ). In mice, loss of ASCL1 in glioma delays tumor progression thereby increasing survival ( Vue et al, 2020 ). In these studies, ASCL1 is shown to both directly and indirectly regulate the expression of cell cycle genes, drivers of neurodevelopment, and factors shown to regulate gliogenesis ( Vue et al, 2020 ).…”

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

“…Lineage tracing experiments in mice have shown that ASCL1 + neural progenitors can be cells of origin of GBM [ 59 , 91 ] and upregulation of ASCL1 and inhibition of NOTCH signaling characterize astrocytoma progression [ 143 ]. ASCL1 expression is maintained in both xenografts from human proneural GBM samples and GBM mouse models, and ASCL1 can induce cell cycle genes and oncogenes, thereby promoting glioma cell proliferation in some contexts [ 122 , 144 , 145 , 146 ]. Accordingly, ASCL1 knockdown or conditional gene knockout prolong survival of glioma-bearing mice [ 145 , 146 ].…”

“…ASCL1 expression is maintained in both xenografts from human proneural GBM samples and GBM mouse models, and ASCL1 can induce cell cycle genes and oncogenes, thereby promoting glioma cell proliferation in some contexts [ 122 , 144 , 145 , 146 ]. Accordingly, ASCL1 knockdown or conditional gene knockout prolong survival of glioma-bearing mice [ 145 , 146 ]. In contrast, high expression of a curated NOTCH-signaling gene set, including HES/HEY transcriptional repressors, correlates with less proliferative glioma cell subpopulations with putative GSC character [ 122 ].…”