Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population.

in Acta neuropathologica communications by Joshua A Regal, María E Guerra García, Vaibhav Jain, Vidyalakshmi Chandramohan, David M Ashley, Simon G Gregory, Eric M Thompson, Giselle Y López, Zachary J Reitman

TLDR

  • The study used high-resolution transcriptomic approaches to characterize the cellular hierarchy of gangliogliomas and identified CD34+ neuroectoderm-like tumor precursor cells that control transcription programs and cell signaling.
  • The findings may guide tumor classification, diagnosis, and therapeutic investigations for gangliogliomas and other glial brain tumors.

Abstract

Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy-confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.

Overview

  • The study aims to refine the classification of gangliogliomas and identify therapeutic approaches by investigating the cellular composition and genetic regulatory network of the tumors.
  • The study analyzed five gangliogliomas using single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq to uncover the cellular hierarchy and gene regulatory networks of the tumors.
  • The primary objective of the study is to identify the CD34+ neuroectoderm-like tumor precursor cells that control transcription programs, cell signaling, and associated immune cell states, which may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.

Comparative Analysis & Findings

  • The study found a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers in the gangliogliomas.
  • Gene regulatory network interrogation revealed that TCF7L2/MEIS1-PAX6 and SOX2 control transcriptional programming in the neuroectoderm-like cells, similar to that found during neuroectodermal/neural development.
  • Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with a relative lack of vascular and immune cells, and a developmental trajectory analysis showed that the neuroectoderm-like tumor cells are precursor cells that give rise to neuron-like and macroglia-like neoplastic cells.

Implications and Future Directions

  • The findings of the study may guide tumor classification, diagnosis, prognostication, and therapeutic investigations for gangliogliomas and other glial brain tumors.
  • The study highlights the importance of investigating the cellular composition and genetic regulatory networks of tumors to develop effective therapeutic approaches.
  • Future studies may investigate the role of CD34+ neuroectoderm-like tumor precursor cells in the development and progression of gangliogliomas and other brain tumors, and explore novel therapeutic strategies targeting these cells.
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