Article
The role of aging induced environmental alterations in glioblastoma
Die Rolle von altersbedingten Veränderungen in der Mikroumgebung beim Glioblastom
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Authors
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Vidhya Madapusi Ravi
- Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Neuroelectronic Systems, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
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Paulina Will
- Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
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Jürgen Beck
- Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
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Ulrich Hofmann
- Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Neuroelectronic Systems, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
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Oliver Schnell
- Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
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Dieter Henrik Heiland
- Medical Center, University of Freiburg, Translational NeuroOncology Research Group, Freiburg, Deutschland; Medical Center, University of Freiburg, Department of Neurosurgery, Freiburg, Deutschland; Medical Center, University of Freiburg, Freiburg, Deutschland
| Published: | June 4, 2021 |
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Outline
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Objective: Aging of the human brain is a multifactorial process that is only partially explored. One major finding is that brain samples acquired from an elderly cohort are enriched with glial cells in comparison to a younger cohort and exhibit inflammatory activation. Due to the fact that glioblastomas mostly arise in older patients, we aimed to explore similarities between the GBM microenvironment and healthy age-related transcriptional alterations.
Methods: We performed spatial transcriptomics using Visium 10X Genomics technology, on 24 specimens and performed meta-module analysis of weighed networks to extract correlations between gene expression modules and clinical characteristics. We used a human neocortical model with different age groups and injected a “young” (45y) or an “old” (86y) patient-derived tumor cell line. We performed single-cell RNA-sequencing of the extracted cell lines to trace back transcriptional dynamics within age-related environments.
Results: We identified a transcriptional signature significantly correlated to age which was shared in non-malignant and tumor samples. This signature was marked by complement activation and expression of typical astrocytic inflammatory genes (GFAP, C3, C1S, C1R, SERPING1, CXCL9), confirmed by immunostainings. Age-related signatures were highly enriched in cells of the reactive subtype (hypoxic or immune reactive subtype) and not expressed in cells of differentiated lineages (NPC-like, OPC-like). In our neocortical slice model, we showed that primary GBM cells from “old” (86y) specimen did not grow in younger tissue microenvironment (2y), altered their morphology in “mid-age” tissue (38y) and proliferate the most in age-matched tissue environment. On the contrary, primary GBM cells from “young” (45y) old specimen showed a similar behavior with the maximum growth-rate in elderly tissue. Single-cell RNA-sequencing confirmed the enrichment of reactive states in elderly tissues.
Conclusion: Our analyses suggest that age-related differences in the human brain are also reflected in glioblastoma. The aging environment is responsible for reactive transcriptional subtypes of glioblastoma and support tumor growth. Our findings support the essential demand for personalized therapy for glioblastoma.
