1. Academic Validation
  2. Extra centrosomes delay DNA damage-driven tumorigenesis

Extra centrosomes delay DNA damage-driven tumorigenesis

  • Sci Adv. 2024 Mar 29;10(13):eadk0564. doi: 10.1126/sciadv.adk0564.
Vincent Z Braun 1 Gerlinde Karbon 1 Fabian Schuler 1 Marina A Schapfl 1 Johannes G Weiss 1 2 Paul Y Petermann 1 Diana C J Spierings 3 Andrea E Tijhuis 3 Floris Foijer 3 Verena Labi 1 Andreas Villunger 1 4
Affiliations

Affiliations

  • 1 Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 2 Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
  • 3 European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
  • 4 The CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Abstract

Deregulated centrosome numbers are frequently found in human Cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood Cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, Caspase-2, Raidd/Cradd, or Pidd1. BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial Apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.

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