Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression
- Cancer Research UK Beatson Institute, United Kingdom
- Ryerson University, Canada
- University of Glasgow, United Kingdom
- Imperial College London, United Kingdom
Abstract
Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating Aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage associated molecular pattern protein HMGB1 or signalling by its cognate receptor TLR4 lowered neutrophil infiltration and reduced liver damage. ROCK1nc mice also developed fewer diethylnitrosamine-induced hepatocellular carcinoma (HCC) tumours, while HMGB1 inhibition increased HCC tumour numbers. Thus, ROCK1 activation and consequent cell contraction are required to limit sterile inflammation and damage amplification following tissue-scale cell death. Additionally, these findings reveal a previously unappreciated role for acute sterile inflammation as an efficient tumour suppressive mechanism.
Data availability
Data generated during this study are presented in the figures. No datasets were generated or used in this study.
Article and author information
Author details
Funding
Cancer Research UK (A10419)
- Linda Julian
- Gregory Naylor
- Grant R Wickman
- Nicola Rath
- David Stevenson
- Sheila Bryson
- June Munro
- Lynn McGarry
- Michael F Olson
Cancer Research UK (A17196)
- Linda Julian
- Gregory Naylor
- Grant R Wickman
- Nicola Rath
- David Stevenson
- Sheila Bryson
- June Munro
- Lynn McGarry
- Michael F Olson
Cancer Research UK (A18276)
- Linda Julian
- Gregory Naylor
- Grant R Wickman
- Nicola Rath
- Michael F Olson
Canada Research Chairs (950-231665)
- Michael F Olson
Natural Sciences and Engineering Research Council of Canada (RGPIN-2020-05388)
- Giovanni Costino
- Michael F Olson
Canadian Institutes of Health Research (PJT-169106)
- Giovanni Costino
- Michael F Olson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse experiments were approved by the University of Glasgow College of Medicine, Veterinary and Life Sciences Research Ethics Committee, and performed under a project license granted by the United Kingdom government Home Office, in line with the Animals (Scientific Procedures) Act 1986 and European Union Directive 2010/63/EU in a dedicated barriered facility.
Copyright
© 2021, Julian 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
-
- 1,387
- views
-
- 163
- downloads
-
- 12
- 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)
Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression
eLife 10:e61983.
https://doi.org/10.7554/eLife.61983
Further reading
-
- Cancer Biology
- Cell Biology
DNA base lesions, such as incorporation of uracil into DNA or base mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair of genomic uracil, we performed a CRISPR knockout screen in the presence of floxuridine, a chemotherapeutic agent that incorporates uracil and fluorouracil into DNA. We identified known factors, such as uracil DNA N-glycosylase (UNG), and unknown factors, such as the N6-adenosine methyltransferase, METTL3, as required to overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, the product of METTL3 activity, N6-methyladenosine, formed nuclear foci in cells treated with floxuridine. The observed N6-methyladenosine was embedded in DNA, called 6mA, and these results were confirmed using an orthogonal approach, liquid chromatography coupled to tandem mass spectrometry. METTL3 and 6mA were required for repair of lesions driven by additional base-damaging agents, including raltitrexed, gemcitabine, and hydroxyurea. Our results establish a role for METTL3 and 6mA in promoting genome stability in mammalian cells, especially in response to base damage.
-
- Cancer Biology
Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
