1. Cancer Biology
Download icon

Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila

  1. Andreas Bergmann  Is a corresponding author
  2. Ernesto Perez
  3. Jillian L Lindblad
  1. University of Massachusetts Medical School, United States
Research Article
  • Cited 33
  • Views 2,542
  • Annotations
Cite this article as: eLife 2017;6:e26747 doi: 10.7554/eLife.26747


Apoptosis and its molecular mediators, the caspases, have long been regarded as tumor suppressors and one hallmark of cancer is “Evading Apoptosis”. However, recent work has suggested that apoptotic caspases can also promote proliferation and tumor growth under certain conditions. How caspases promote proliferation and how cells are protected from the potentially harmful action of apoptotic caspases is largely unknown. Here, we show that although caspases are activated in a well-studied neoplastic tumor model in Drosophila, oncogenic mutations of the proto-oncogene Ras (RasV12) maintain tumorous cells in an “undead”-like condition and transform caspases from tumor suppressors into tumor promotors. Instead of killing cells, caspases now promote the generation of intra- and extracellular reactive oxygen species (ROS). One function of the ROS is the recruitment and activation of macrophage-like immune cells which in turn signal back to tumorous epithelial cells to activate oncogenic JNK signaling. JNK further promotes and amplifies caspase activity, thereby constituting a feedback amplification loop. Interfering with the amplification loop strongly reduces the neoplastic behavior of these cells and significantly improves organismal survival. In conclusion, RasV12-modified caspases initiate a feedback amplification loop involving tumorous epithelial cells and macrophage-like immune cells that is necessary for uncontrolled tumor growth and invasive behavior.

Article and author information

Author details

  1. Andreas Bergmann

    Department of Molecular, cell and cancer biology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9134-871X
  2. Ernesto Perez

    Department of Molecular, cell and cancer biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jillian L Lindblad

    Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.


National Institute of General Medical Sciences (R35GM118330)

  • Andreas Bergmann

National Institute of General Medical Sciences (R01GM107789)

  • Andreas Bergmann

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

Reviewing Editor

  1. Helen McNeill, University of Toronto, Canada

Publication history

  1. Received: March 13, 2017
  2. Accepted: August 28, 2017
  3. Accepted Manuscript published: August 30, 2017 (version 1)
  4. Version of Record published: September 21, 2017 (version 2)


© 2017, Bergmann 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.


  • 2,542
    Page views
  • 645
  • 33

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

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. Biochemistry and Chemical Biology
    2. Cancer Biology
    Lavanya H Palavalli Parsons et al.
    Research Article

    PARP-7 (TiPARP) is a mono(ADP-ribosyl) transferase whose proteins substrates and biological activities are poorly understood. We observed that PARP7 mRNA levels are lower in ovarian cancer patient samples compared to non-cancerous tissue, but PARP-7 protein nonetheless contributes to several cancer-related biological endpoints in ovarian cancer cells (e.g., growth, migration). Global gene expression analyses in ovarian cancer cells subjected to PARP-7 depletion indicate biological roles for PARP-7 in cell-cell adhesion and gene regulation. To identify the MARylated substrates of PARP-7 in ovarian cancer cells, we developed an NAD+ analog-sensitive approach, which we coupled with mass spectrometry to identify the PARP-7 ADP-ribosylated proteome in ovarian cancer cells, including cell-cell adhesion and cytoskeletal proteins. Specifically, we found that PARP-7 MARylates α-tubulin to promote microtubule instability, which may regulate ovarian cancer cell growth and motility. In sum, we identified an extensive PARP-7 ADP-ribosylated proteome with important roles in cancer-related cellular phenotypes.

    1. Cancer Biology
    2. Stem Cells and Regenerative Medicine
    Madeline Sandoval et al.
    Research Article Updated

    Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intraclonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.