Department of Neurosciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.
Nat Commun. 2024 Nov 28;15(1):10363. doi: 10.1038/s41467-024-54750-9.
Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other's loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
胶质母细胞瘤（GBM）是由复杂的遗传改变驱动的高度侵袭性、浸润性和异质性脑肿瘤。碱性螺旋-环-螺旋（bHLH）转录因子 ASCL1 和 OLIG2 在 GBM 中动态共表达；然而，它们在调节 GBM 细胞可塑性和异质性方面的组合作用尚不清楚。在这里，我们表明诱导侧脑室下区（SVZ）祖细胞中的体细胞突变会导致 ASCL1 和 OLIG2 的失调，随后它们以冗余的方式发挥作用，并需要在 GBM 的小鼠模型中形成脑肿瘤。随后，ASCL1 和 OLIG2 彼此的基因座和下游靶基因的结合决定了肿瘤细胞的类型和迁移程度。单细胞 RNA 测序（scRNA-seq）揭示，高水平的 ASCL1 是指定具有高迁移能力的神经干细胞（NSC）/星形胶质细胞样肿瘤细胞类型的关键，其特征是核糖体蛋白、氧化磷酸化、癌症转移和治疗耐药基因的上调。
