Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Sci Adv. 2024 Mar 29;10(13):eadk0564. doi: 10.1126/sciadv.adk0564.
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, , , or . 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.
中心体数量失调经常在人类癌症中发现，并能促进模型生物中的恶性肿瘤。目前的研究旨在阐明额外的中心体是恶性转化的原因还是结果，以及它们的发生是否可以作为治疗的靶点。在这里，我们表明，癌基因驱动的血液癌对中心体数量的遗传操作不敏感，而 DNA 损伤诱导的恶性肿瘤的形成则被延迟。我们首次提供证据表明，这种意外现象与额外的中心体引发参与凋亡机制的促死亡信号有关。凋亡诱导需要 PIDDosome 多蛋白复合物，因为它可以通过其三个组成部分、、或的缺失来阻断，同样地，BCL2 的过表达也能阻止细胞死亡，这首次证明了线粒体凋亡下游的额外中心体诱导。我们的研究结果表明，在转化过程中中心体扩增具有上下文依赖性，并要求调整目前认为额外的中心体本质上是促肿瘤发生的观点。
