Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation
- University of Edinburgh, United Kingdom
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 4 and 5.
Article and author information
Author details
Funding
Cancer Research UK (C49916/A17494)
- Dirk Sieger
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal experimentation: Animal experimentation was reviewed and approved by the ethical review committee of the University of Edinburgh and the Home Office (Project license 60/4544 + P5042DEFB), in accordance with the Scientific Procedure Act 1986.
Copyright
© 2019, Chia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation
eLife 8:e46912.
https://doi.org/10.7554/eLife.46912
