Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma

Abstract

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.

Glioma Stem Cells in Pediatric High-Grade Gliomas: From Current Knowledge to Future Perspectives

“…We will also discuss the more recent insight into GSC generation and maintenance in pHGG (3.3) (Figure 2). Although beyond the scope of the present review, note that CSCs have also been described in other childhood brain cancers, especially in embryonal tumors [30,35,[49][50][51] and ependymomas [52][53][54][55]. In these tumors, many of the following molecular markers and phenotypic features were also used for CSC identification and characterization.…”

Long-read sequencing for brain tumors

“…As previously mentioned, epigenetics plays a crucial role in carcinogenesis ( 116 , 155 ). This term, which was initially introduced by Conrad Waddington in 1942 as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” ( 156 , 157 ), has been extensively studied in the recent years as there are known mechanisms that modify chromatin structure and have been reported to be crucial in various and aggressive CNS tumors such as GBM ( 158 – 160 ), medulloblastoma ( 161 – 163 ), ependymoma ( 164 , 165 ), diffuse intrinsic pontine gliomas ( 166 , 167 ), meningioma ( 147 ), among others. The epigenetic modifications that are capable of modifying chromatin structure are encompassed into four categories: DNA methylation, histone modifications, and non-covalent mechanisms (e.g., nucleosome remodeling, non-coding RNAs) ( 155 ).…”

Complex Elucidation of Cells-of-Origin in Pediatric Soft Tissue Sarcoma: From Concepts to Real Life, Hide-and-Seek through Epigenetic and Transcriptional Reprogramming

“…These findings support the view that developmental programs are recapitulated in many diverse solid tumor types, such as medulloblastoma [ 99 ] and melanoma [ 100 ]. Single-cell RNA sequencing (scRNA-seq) data have reinforced the interest in these comparative transcriptomic approaches as tools to characterize the lineage of origin of tumor cells by trajectory inferences analyses [ 101 , 102 ]. Moreover, even poorly differentiated tumor cells might preserve a lineage memory that reflects their developmental history [ 103 , 104 ].…”