PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis

Sladky, V. C.; Knapp, K.; Szabo, T. G.; Bongiovanni, L.; van den Bos, H.; Spierings, D. C. J.; Westendorp, B.; Stojakovic, T.; Scharnagl, H.; Timelthaler, G.; Tsuchia, K.; Pinter, M.; Foijer, F.; de Bruin, A.; Reiberger, T.; Rohr-Udilova, N.; Villunger, A.

doi:10.1101/2020.05.13.092486

bioRxiv · 10.1101/2020.05.13.092486

PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis

Sladky, V. C.·Knapp, K.·Szabo, T. G.·Bongiovanni, L.·van den Bos, H.·Spierings, D. C. J.·Westendorp, B.·Stojakovic, T.·Scharnagl, H.·Timelthaler, G.·Tsuchia, K.·Pinter, M.·Foijer, F.·de Bruin, A.·Reiberger, T.·Rohr-Udilova, N.·Villunger, A.

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Abstract

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome-deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome-deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome-deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts of survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.

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Sladky, V. C., Knapp, K., Szabo, T. G., Bongiovanni, L., van den Bos, H., Spierings, D. C. J., Westendorp, B., Stojakovic, T., Scharnagl, H., Timelthaler, G., Tsuchia, K., Pinter, M., Foijer, F., de Bruin, A., Reiberger, T., Rohr-Udilova, N., Villunger, A.. 2020-05-14. PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis. https://doi.org/10.1101/2020.05.13.092486

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