Caspase-2 and the PIDDosome do not control aneuploidy in hepatocellular carcinoma

The PIDDosome is a multimeric protein complex that activates caspase-2 in response to supernumerary centrosomes. In polyploid hepatocytes, this pathway is activated to induce a p53-depenent cell cycle arrest. Thereby, the PIDDosome controls the upper limit of hepatic ploidy during development and regeneration. Since caspase-2 has been suggested to delete aneuploid cancer cells [1, 2], we employed single cell sequencing techniques to test whether caspase-2 itself or caspase-2 mediated p53 activation are involved in this process during hepatocarcinogenesis. Murine liver tumors were induced using diethylnitrosamine (DEN, 25mg /kg, i.p.) injected at the age of 15 days and analyzed 10 months later. Nuclei of tumor tissue of ten wt or caspase-2 deficient mice were isolated and per tumor 30 diploid and tetraploid cells were sorted and sequenced in bulk. Our data suggest that tetraploid tumor cells tend to have a higher degree of aneuploidy which is independent of caspase-2 as both wt and caspase-2 deficient tumors showed a similar degree of copy number variation. 1) López-García, C., Sansregret, L., Domingo, E., McGranahan, N., Hobor, S., Birkbak, N. J., … Swanton, C. (2017). BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer. Cancer Cell, 31(1), 79–93. https://doi.org/10.1016/j.ccell.2016.11.0012) Dawar, S., Lim, Y., Puccini, J., White, M., Thomas, P., Bouchier-Hayes, L., … Kumar, S. (2017). Caspase-2-mediated cell death is required for deleting aneuploid cells. Oncogene, 36(19), 2704–2714. https://doi.org/10.1038/onc.2016.423