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

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.

Data availability

All data used during this study was obtained from the public databases indicated in the manuscript.Results generated during this study are included as supporting files.

The following previously published data sets were used

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.

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

  • 3,995
    views
  • 590
    downloads
  • 57
    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. Anna S Trigos
  2. Richard B Pearson
  3. Anthony T Papenfuss
  4. David L Goode
(2019)
Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer
eLife 8:e40947.
https://doi.org/10.7554/eLife.40947

Share this article

https://doi.org/10.7554/eLife.40947

Further reading

    1. Cancer Biology
    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology
    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.