From sorting to sequencing in the molecular era: the evolution of the cancer stem cell model in medulloblastoma

Abstract

The cancer stem cell (CSC) model posits that tumors contain subpopulations that display defining features of normal stem cells including self-renewal capacity and differentiation. Tumor cells exhibiting these features are now considered to be responsible for tumor propagation and drug resistance in a wide variety of cancers. Therefore, identification of robust CSC markers and characterization of CSC-specific molecular signatures may lead to identification of novel therapeutics that selectively abolish this clinically relevant cell population while preserving normal tissue. Brain tumor researchers have been at the forefront of the CSC field. From initial in vitro cell sorting experiments to the sophisticated bioinformatics technologies that now exquisitely resolve primary brain tumors at a single cell level, recent glioma and medulloblastoma (MB) studies have integrated developmental state with genomic and transcriptome data to identify the spectrum of cell types that may drive tumor progression. This review will examine the last two decades of CSC studies in the field. Seminal discoveries, emerging controversies and outstanding questions will be covered with a particular focus on MB, the most common malignant primary brain tumor in children.

Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma

“…G3 MB cells are thought to originate from neural progenitor populations that arise during rhombic lip development, and these malignant counterparts maintain stem-cell properties such as the ability to self-renew and undergo multi-lineage differentiation, which contributes to their aggressive nature 29 , 30 . Moreover, MYC is known to support stem-cell maintenance and inhibit differentiation 31 .…”

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review

“…During the early exploration of the origins of CSCs in medulloblastoma, specialists noticed that alterations in the critical SHH signalling pathway for regulating proliferation on the granule neuron precursor could induce SHH subgroup medulloblastoma, which led researchers to consider the possibility that different medulloblastoma subtypes arose from CSCs with distinct cell lineages [ 148 ]. Recently, it has become clear that lineage-specific molecular signatures in medulloblastoma CSC played a decisive role in the formation of four molecular subgroups of medulloblastomas [ 149 ]. They were protein patched homolog 1 (PTCH1)-deleted CSCs with granule neuron progenitors or a neural stem cell lineage, WNT alterations in CSCs matched to the lower rhombic lip pontine mossy fibre lineage in the brainstem, CSCs with a mixed population of malignant cells with divergent differentiation along the cerebellar lineage, or CSCs closely associated with a neuronal differentiation metaprogram and the unipolar brush cell lineage arising from the upper rhombic lip.…”