PUBLICATION
Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation
- Authors
- Chia, K., Keatinge, M., Mazzolini, J., Sieger, D.
- ID
- ZDB-PUB-190719-11
- Date
- 2019
- Source
- eLIFE 8: (Journal)
- Registered Authors
- Keatinge, Marcus, Sieger, Dirk
- Keywords
- cancer biology, neuroscience, zebrafish
- MeSH Terms
-
- Adenosine Triphosphate/metabolism
- Animals
- Brain Neoplasms/pathology*
- Calcium/metabolism
- Cell Communication
- Cell Line, Tumor
- Cell Proliferation
- Microglia/metabolism
- Microglia/pathology*
- Neurons/metabolism
- Neurons/pathology*
- Proto-Oncogene Proteins c-akt/metabolism
- Receptors, Purinergic P2Y12/metabolism
- Signal Transduction*
- Zebrafish
- PubMed
- 31313988 Full text @ Elife
Citation
Chia, K., Keatinge, M., Mazzolini, J., Sieger, D. (2019) Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation. eLIFE. 8:.
Abstract
Previously we described direct cellular interactions between microglia and AKT1+ brain tumour cells in zebrafish (Chia et al., 2018). However, it was unclear how these interactions were initiated: it was also not clear if they had an impact on the growth of tumour cells. Here, we show that neoplastic cells hijack mechanisms that are usually employed to direct microglial processes towards highly active neurons and injuries in the brain. We show that AKT1+ cells possess dynamically regulated high intracellular Ca2+ levels. Using a combination of live imaging, genetic and pharmacological tools we show that these Ca2+ transients stimulate ATP mediated interactions with microglia. Interfering with Ca2+ levels, inhibiting ATP release and CRISPR mediated mutation of the p2ry12 locus abolishes these interactions. Finally, we show that reducing the number of microglial interactions significantly impairs the proliferation of neoplastic AKT1 cells. In conclusion, neoplastic cells repurpose the endogenous neuron to microglia signalling mechanism via P2ry12 activation to promote their own proliferation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping