1. Cancer Biology
  2. Computational and Systems Biology
Download icon

Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer

  1. Anna S Trigos
  2. Richard B Pearson
  3. Anthony T Papenfuss
  4. David L Goode  Is a corresponding author
  1. Peter MacCallum Cancer Centre, Australia
  2. The University of Melbourne, Australia
Research Article
  • Cited 5
  • Views 2,554
  • Annotations
Cite this article as: eLife 2019;8:e40947 doi: 10.7554/eLife.40947

Abstract

Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumours, we show many transcriptional changes in tumours are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.

Article and author information

Author details

  1. Anna S Trigos

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Richard B Pearson

    Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Anthony T Papenfuss

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. David L Goode

    Computational Cancer Biology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
    For correspondence
    david.goode@petermac.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3277-6562

Funding

University of Melbourne

  • Anna S Trigos

National Health and Medical Research Council

  • Richard B Pearson
  • Anthony T Papenfuss
  • David L Goode

The Peter MacCallum Cancer Centre Foundation

  • David L Goode

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Alfonso Valencia, Barcelona Supercomputing Center - BSC, Spain

Publication history

  1. Received: August 9, 2018
  2. Accepted: February 6, 2019
  3. Accepted Manuscript published: February 26, 2019 (version 1)
  4. Version of Record published: March 6, 2019 (version 2)

Copyright

© 2019, Trigos 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

  • 2,554
    Page views
  • 402
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Cancer Biology
    Zeyad D Nassar et al.
    Research Article Updated

    Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.

    1. Cancer Biology
    2. Human Biology and Medicine
    Jaime N Wertman et al.
    Research Article

    Dose-limiting toxicities for cisplatin administration, including ototoxicity and nephrotoxicity, impact the clinical utility of this effective chemotherapy agent and lead to lifelong complications, particularly in pediatric cancer survivors. Using a two-pronged drug screen employing the zebrafish lateral line as an in vivo readout for ototoxicity and kidney cell-based nephrotoxicity assay, we screened 1280 compounds and identified 22 that were both oto- and nephroprotective. Of these, dopamine and L-mimosine, a plant-based amino acid active in the dopamine pathway, were further investigated. Dopamine and L-mimosine protected the hair cells in the zebrafish otic vesicle from cisplatin-induced damage and preserved zebrafish larval glomerular filtration. Importantly, these compounds did not abrogate the cytotoxic effects of cisplatin on human cancer cells. This study provides insights into the mechanisms underlying cisplatin-induced oto- and nephrotoxicity and compelling preclinical evidence for the potential utility of dopamine and L-mimosine in the safer administration of cisplatin.