Single-cell and spatial analyses to decipher the unique invasive growth pattern of gliomatosis cerebri
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Embargo End Date
2025-04-02
ICR Authors
Authors
Crampsie, S
Document Type
Thesis or Dissertation
Date
2024-10-02
Date Accepted
Abstract
Gliomatosis cerebri (GC) is a rare, lethal glioma that is radiologically diagnosed and characterised by its diffuse infiltration throughout the cerebral lobes of the brain. It is no longer recognised as a separate entity by the WHO classification, but its growth pattern and invasive phenotype differ from other types of glioma. To understand what underlies this unique presentation, this project sought to unravel these differences through single-cell and spatial approaches. 26 paediatric cases (1.3-19 years, median=11.3) were collected for DNA methylation, whole exome sequencing and single-cell RNA-sequencing. Of these, 17 had FFPE tissue available and were used for Imaging Mass Cytometry (IMC) to analyse the spatial components of this illness. Included in this thesis is contribution to an international retrospective study by the European Society for Paediatric Oncology (SIOPE) exploring the molecular and clinical aspects of GC. The following work uses single-cell-based technologies in collaboration with Dana Farber Cancer Institute, Boston, US and Bambino Gesù Children's Hospital, Rome, Italy. The transcriptional landscape of all 26 GC patients was analysed at single-cell resolution, and shared tumour cellular programs with a predominance of glial, neuronal and migratory programmes were identified. Analysing multiple regions of interest within FFPE patient tissue sections by IMC, this work demonstrates the spatial patterns of GC in the interaction between the tumour and normal brain tissue interface, as well as inter-regional heterogeneity for stem, invasive and proliferative markers. The development and acquirement of GC patient-derived cell lines were used to model migration and invasion in vitro, and have also been used to explore gene expression differences associated with the invading cells by RNA sequencing. This thesis studies the invasive phenotype of GC at multiple molecular, spatial and functional layers, with the aim of providing the basis for modelling and therapeutic avenues in the future.
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Glioma Team