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Journal articles
Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse
Aladin Haimovici
1
Christoph Höfer
1
Mohamed Tarek Badr
1
Elham Bavafaye Haghighi
1
Tarek Amer
1
Melanie Boerries
1, 2
Peter Bronsert
1
Ievgen Glavynskyi
1
Deborah Fanfone
3, 4
Gabriel Ichim
3, 4
Nico Thilmany
1
Arnim Weber
1
Tilman Brummer
1, 2
Corinna Spohr
1
Rupert Öllinger
5
Klaus-Peter Janssen
5
Roland Rad
5
Georg Häcker
1
Aladin Haimovici 1
Author ORCID : https://orcid.org/0000-0001-7455-7790
Christoph Höfer 1
Author ORCID : https://orcid.org/0000-0002-3169-3992
Mohamed Tarek Badr 1
Author ORCID : https://orcid.org/0000-0002-8800-6380
Elham Bavafaye Haghighi 1
Author
Deborah Fanfone 3, 4
Author ORCID : https://orcid.org/0000-0002-3909-8143
Gabriel Ichim 3, 4
Author
Nico Thilmany 1
Author ORCID : https://orcid.org/0000-0003-1039-4173
Arnim Weber 1
Author
Tilman Brummer 1, 2
Author ORCID : https://orcid.org/0000-0003-4387-7905
Corinna Spohr 1
Author ORCID : https://orcid.org/0000-0002-9781-4443
Rupert Öllinger 5
Author
Klaus-Peter Janssen 5
Author
Roland Rad 5
Author
Georg Häcker 1
Author ORCID : https://orcid.org/0000-0003-1058-5746
1
University of Freiburg [Freiburg] (Friedrichstr. 39 79098 Freiburg - Germany)
2
DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (German Cancer Research Center Im Neuenheimer Feld 280 D-69120 Heidelberg - Germany)
3
UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon (28, rue Laennec - 69373 Lyon - France)
- Centre Léon Bérard [Lyon] (28, rue Laennec 69373 LYON Cedex 08 - France)
- UCBL - Université Claude Bernard Lyon 1 (43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
- CNRS - Centre National de la Recherche Scientifique : UMR5286 (France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1052 (101, rue de Tolbiac, 75013 Paris - France)
4
LabEx DEVweCAN - Développement Cancer et Thérapies Ciblées [Lyon] (28 rue Laennec 69008 Lyon - France)
- Université de Lyon (92 rue Pasteur - CS 30122, 69361 Lyon Cedex 07 - France)
5
TUM - Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (Arcisstrasse 21, D- 80333 München - Germany)
Abstract : Abstract Micronuclei are DNA-containing structures separate from the nucleus found in cancer cells. Micronuclei are recognized by the immune sensor axis cGAS/STING, driving cancer metastasis. The mitochondrial apoptosis apparatus can be experimentally triggered to a non-apoptotic level, and this can drive the appearance of micronuclei through the Caspase-activated DNAse (CAD). We tested whether spontaneously appearing micronuclei in cancer cells are linked to sub-lethal apoptotic signals. Inhibition of mitochondrial apoptosis or of CAD reduced the number of micronuclei in tumor cell lines as well as the number of chromosomal misalignments in tumor cells and intestinal organoids. Blockade of mitochondrial apoptosis or deletion of CAD reduced, while experimental activation CAD, STING-dependently, enhanced aggressive growth of tumor cells in vitro. Deletion of CAD from human cancer cells reduced metastasis in xenograft models. CAD-deficient cells displayed a substantially altered gene-expression profile, and a CAD-associated gene expression ‘signature’ strongly predicted survival in cancer patients. Thus, low-level activity in the mitochondrial apoptosis apparatus operates through CAD-dependent gene-induction and STING-activation and has substantial impact on metastasis in cancer.
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Journal articles
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https://hal-univ-lyon1.archives-ouvertes.fr/hal-03667748
Contributor : Brigitte Manship Connect in order to contact the contributor
Submitted on : Friday, May 13, 2022 - 3:31:20 PM
Last modification on : Monday, May 16, 2022 - 10:10:25 AM
Contributor : Brigitte Manship Connect in order to contact the contributor
Submitted on : Friday, May 13, 2022 - 3:31:20 PM
Last modification on : Monday, May 16, 2022 - 10:10:25 AM
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- HAL Id : hal-03667748, version 1
- DOI : 10.1038/s41419-022-04768-y
- PUBMED : 35393399
- PUBMEDCENTRAL : PMC8990075
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UNIV-LYON1 | CRCL | UDL | CNRS | INSERM
Citation
Aladin Haimovici, Christoph Höfer, Mohamed Tarek Badr, Elham Bavafaye Haghighi, Tarek Amer, et al.. Spontaneous activity of the mitochondrial apoptosis pathway drives chromosomal defects, the appearance of micronuclei and cancer metastasis through the Caspase-Activated DNAse. Cell Death and Disease, Nature Publishing Group, 2022, 13 (4), pp.315. ⟨10.1038/s41419-022-04768-y⟩. ⟨hal-03667748⟩
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