Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma.
Dieter Henrik HeilandVidhya M RaviSimon P BehringerJan Hendrik FrenkingJulian WurmKevin JosephNicklas W C GarrelfsJakob SträhleSabrina HeynckesJürgen GrauvogelPamela FrancoIrina MaderMatthias SchneiderAnna-Laura PotthoffDaniel DelevUlrich G HofmannChristian FungJürgen BeckRoman SankowskiMarco PrinzOliver SchnellPublished in: Nature communications (2019)
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.
Keyphrases
- brain injury
- rna seq
- gene expression
- single cell
- inflammatory response
- subarachnoid hemorrhage
- endothelial cells
- neuropathic pain
- induced apoptosis
- dna methylation
- computed tomography
- transcription factor
- magnetic resonance imaging
- spinal cord injury
- epithelial mesenchymal transition
- cell death
- spinal cord
- cell cycle arrest
- cell proliferation
- heat shock protein
- cerebrospinal fluid
- blood brain barrier