3D Brain Vascular Niche Model Captures Glioblastoma Infiltration, Dormancy, and Gene Signatures.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Vivian K Lee, Rut Tejero, Nathaniel Silvia, Anirudh Sattiraju, Aarthi Ramakrishnan, Li Shen, Alexandre Wojcinski, Santosh Kesari, Roland H Friedel, Hongyan Zou, Guohao Dai

TLDR

  • This study developed a 3D brain vascular niche model to study glioblastoma cell behavior and found that glia-vascular contact induces specific gene signatures associated with poor prognosis.
  • These findings have implications for understanding GBM progression and developing effective treatments.

Abstract

Glioblastoma (GBM) is a lethal brain cancer with no effective treatment; understanding how GBM cells respond to tumor microenvironment remains challenging as conventional cell cultures lack proper cytoarchitecture while in vivo animal models present complexity all at once. Developing a culture system to bridge the gap is thus crucial. Here, a multicellular approach is employed using human glia and vascular cells to optimize a 3D brain vascular niche model that enabled not only long-term culture of patient derived GBM cells but also recapitulation of key features of GBM heterogeneity, in particular invasion behavior and vascular association. Comparative transcriptomics of identical patient derived GBM cells in 3D and in vivo xenotransplants models revealed that glia-vascular contact induced genes concerning neural/glia development, synaptic regulation, as well as immune suppression. This gene signature displayed region specific enrichment in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis. Gene variance analysis also uncovered histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo. Furthermore, the 3D model also demonstrated the capacity to provide a quiescence and a protective niche against chemotherapy.

Overview

  • The study aims to develop a 3D brain vascular niche model to understand how glioblastoma (GBM) cells respond to the tumor microenvironment, which is challenging due to the limitations of conventional cell cultures and in vivo animal models.
  • The multicellular approach uses human glia and vascular cells to optimize the 3D model, enabling long-term culture of patient-derived GBM cells and recapitulation of key features of GBM heterogeneity, such as invasion behavior and vascular association.
  • The study compares the transcriptomics of patient-derived GBM cells in the 3D model and in vivo xenotransplant models to understand the impact of glia-vascular contact on gene expression and identify region-specific signatures associated with GBM progression and prognosis.

Comparative Analysis & Findings

  • The study found that glia-vascular contact induces genes related to neural/glia development, synaptic regulation, and immune suppression in patient-derived GBM cells cultured in the 3D model.
  • Comparative transcriptomics analysis revealed that the gene signature was region-specifically enriched in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis.
  • Gene variance analysis identified histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo, suggesting that these processes may play important roles in GBM progression and resistance to chemotherapy.

Implications and Future Directions

  • The study highlights the importance of understanding how GBM cells interact with the tumor microenvironment to develop effective treatments for this devastating disease.
  • Future studies should investigate the molecular mechanisms underlying the region-specific gene signature and gene adaptation in GBM cells in vivo, as well as the potential therapeutic implications of these findings.
  • The 3D model may be used as a tool to predict patient responses to chemotherapy and identify novel targets for therapy, potentially leading to improved outcomes for GBM patients.
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