Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation

  1. Kelda Chia
  2. Marcus Keatinge
  3. Julie Mazzolini
  4. Dirk Sieger  Is a corresponding author
  1. 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

  1. Kelda Chia

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Marcus Keatinge

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Julie Mazzolini

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Dirk Sieger

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    dirk.sieger@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6881-5183

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.

Metrics

  • 3,293
    views
  • 455
    downloads
  • 23
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Kelda Chia
  2. Marcus Keatinge
  3. Julie Mazzolini
  4. Dirk Sieger
(2019)
Brain tumours repurpose endogenous neuron to microglia signalling mechanisms to promote their own proliferation
eLife 8:e46912.
https://doi.org/10.7554/eLife.46912

Share this article

https://doi.org/10.7554/eLife.46912

Further reading

    1. Cancer Biology
    2. Medicine
    Patrick Brandt, Dawayne Whittington ... Rebekah L Layton
    Research Article

    A doctoral-level internship program was developed at the University of North Carolina at Chapel Hill with the intent to create customizable experiential learning opportunities for biomedical trainees to support career exploration, preparation, and transition into their postgraduate professional roles. We report the outcomes of this program over a 5-year period. During that 5-year period, 123 internships took place at over 70 partner sites, representing at least 20 academic, for-profit, and non-profit career paths in the life sciences. A major goal of the program was to enhance trainees’ skill development and expertise in careers of interest. The benefits of the internship program for interns, host/employer, and supervisor/principal investigator were assessed using a mixed-methods approach, including surveys with closed- and open-ended responses as well as focus group interviews. Balancing stakeholder interests is key to creating a sustainable program with widespread support; hence, the level of support from internship hosts and faculty members were the key metrics analyzed throughout. We hypothesized that once a successful internship program was implemented, faculty culture might shift to be more accepting of internships; indeed, the data quantifying faculty attitudes support this. Furthermore, host motivation and performance expectations of interns were compared with results achieved, and this data revealed both expected and surprising benefits to hosts. Data suggests a myriad of benefits for each stakeholder group, and themes are cataloged and discussed. Program outcomes, evaluation data, policies, resources, and best practices developed through the implementation of this program are shared to provide resources that facilitate the creation of similar internship programs at other institutions. Program development was initially spurred by National Institutes of Health pilot funding, thereafter, successfully transitioning from a grant-supported model, to an institutionally supported funding model to achieve long-term programmatic sustainability.

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Ashley L Cook, Surojit Sur ... Nicolas Wyhs
    Research Article

    Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.