Abstract

Simple SummaryIntra-cranial ependymoma (EPN) accounts for approximately 10% of pediatric brain tumors. The current therapeutic strategies have not significantly improved prognosis, which is still dismal in nearly 40% of patients. Major challenges for treatment are chemorefractoriness of EPN, tendency to recur, and high intra-tumoral heterogeneity (ITH). It is increasingly emerging that stalled neurodevelopmental programs driven by cancer stem cells (CSCs)/progenitor cells are at the root of oncogenesis and ITH of pediatric brain tumors, including EPN. This is the first review that examines how genetic and heritable epigenetic alterations and environmental selection forces drive ITH of pediatric intra-cranial EPN in the perspective of the CSC model. This review also summarizes how improvement in the single-cell technology has deepened the comprehension of the complexity, cell-of-origin, and developmental trajectories of EPN, paving the way for novel therapeutic options.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.

Highlights

  • Tumors are complex ecosystems composed of non-malignant and malignant cell populations [1]

  • The mastermind like domain containing 1 (MAMLD1) domain is necessary for translocation of the fusion in the nucleus and for the interaction with NFI transcription factors (TFs), that in turn recruit the fusion protein to enhancer regions enriched in TEAD and NFI-binding motifs to drive the transforming gene expression of YAP1-MAMLD1 EPN [39,110]

  • High epigenetic heterogeneity at enhancers has been reported in ESCs [129] and during progression from normal tissues to primary tumors and to metastases with a cancer-specific pattern [130], which indicates that enhancer DNA methylation may be primed to respond to microenvironmental cues and to increase cancer cell plasticity

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Summary

Introduction

Tumors are complex ecosystems composed of non-malignant and malignant cell populations [1]. It is likely that the clonal evolution model and the CSC model coexist and act together in a cooperative manner to determine ITH. In this light, tumors might be considered as an “organ system”, where the cellular subclones act as “tissue types” with distinct functions [13] and reciprocal signaling between tumor subpopulations [14–16] and between tumor and the surrounding microenvironment [17], with complex interactions to enhance tumor fitness and facilitate immune evasion [18], drug resistance [19], and metastasis [20]. RNA sequencing (scRNA-seq) has contributed to the understanding of the complexity and developmental origins of EPN, unraveling some common transcriptional programs across different EPN subtypes, and even across different pediatric brain tumors, which might help define potential druggable vulnerabilities.

Inter-Tumoral
The CSC Model
Intra-tumoral
CSC-Driven Preclinical
Genetic ITH
CSCs and Genomic Instability
Epigenetic ITH
CSCs and Epigenetic Alterations
Schematics
The Perivascular TME
The Hypoxic TME
ITH of EPN: A Single-Cell Perspective
EPN Is Composed of Multiple Discrete Neoplastic Subpopulations
PF-EPN and scRNA-seq
ST-EPN and scRNA-seq
The Cell of Origin and Developmental Trajectories of EPN from an scRNA-seq Perspective
Findings
Concluding Remarks
Full Text
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