The Polyploid State Plays a Tumor-Suppressive Role in the Liver
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Abstract
Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor-suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.
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E2f7 and E2f8, as well as polyploidy, suppress tumorigenesis.
“E2f7 and E2f8, as well as polyploidy, are known to suppress tumorigenesis (43–46).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [44]
The Results section ('E2f8 knockout and Anln shRNA mice confirmed the protective effects of polyploidy'; page unavailable) reports more liver tumors in E2f8-deficient mice, but attributes the difference chiefly to their lower ploidy rather than to E2f8 itself. The Introduction (page unavailable) mentions E2f7/E2f8 double-knockout livers but does not establish a tumor-suppressive role for E2f7. The source supports polyploidy's protective effect in the liver, not the full claim that both genes and polyploidy each suppress tumorigenesis. (LLM, conf=0.88)
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Cites
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863 · see citing works
Tracking the Evolution of Non–Small-Cell Lung Cancer
Jamal-Hanjani, M., Wilson, G. A., McGranahan, N., Birkbak, N. J., Watkins, T. B. K., Veeriah, S., Shafi, S., Johnson, D. H., Mitter, R., Rosenthal, R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1616288 · Cited by 2,349 · see citing works
The advantages and disadvantages of being polyploid
Comai, L. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1711 · Cited by 2,308 · see citing works
CRISPR-Cas9 Knockin Mice for Genome Editing and Cancer Modeling
Platt, R. J., Chen, S., Zhou, Y., Yim, M. J., Swiech, L., Kempton, H. R., Dahlman, J. E., Parnas, O., Eisenhaure, T. M., Jovanovic, M., et al. (2014) · Cell · doi:10.1016/j.cell.2014.09.014 · Cited by 2,001 · see citing works
Pan-cancer patterns of somatic copy number alteration
Zack, T. I., Schumacher, S. E., Carter, S. L., Cherniack, A. D., Saksena, G., Tabak, B., Lawrence, M. S., Zhang, C., Wala, J. A., Mermel, C. H., et al. (2013) · Nature Genetics · doi:10.1038/ng.2760 · Cited by 1,843 · see citing works
Global burden of aflatoxin-induced hepatocellular carcinoma: A risk assessment
Liu, Y., & Wu, F. (2010) · Environmental Health Perspectives · doi:10.1289/ehp.0901388 · Cited by 1,224 · see citing works
The Evolutionary Consequences of Polyploidy
Otto, S. P. (2007) · Cell · doi:10.1016/j.cell.2007.10.022 · Cited by 1,188 · see citing works
Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells
Fujiwara, T., Bandi, M., Nitta, M., Ivanova, E. V., Bronson, R. T., & Pellman, D. (2005) · Nature · doi:10.1038/nature04217 · Cited by 1,067 · see citing works
MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer
Shachaf, C. M., Kopelman, A. M., Arvanitis, C., Karlsson, Å., Beer, S., Mandl, S., Bachmann, M. H., Borowsky, A. D., Ruebner, B., Cardiff, R. D., et al. (2004) · Nature · doi:10.1038/nature03043 · Cited by 874 · see citing works
Davoli, T., Xu, A. W., Mengwasser, K. E., Sack, L. M., Yoon, J. C., Park, P. J., & Elledge, S. J. (2013) · Cell · doi:10.1016/j.cell.2013.10.011 · Cited by 815 · see citing works
CRISPR-mediated direct mutation of cancer genes in the mouse liver
Xue, W., Chen, S., Yin, H., Tammela, T., Papagiannakopoulos, T., Joshi, N. S., Cai, W., Yang, G., Bronson, R., Crowley, D. G., et al. (2014) · Nature · doi:10.1038/nature13589 · Cited by 776 · see citing works
Aneuploidy Acts Both Oncogenically and as a Tumor Suppressor
Weaver, B. A. A., Silk, A. D., Montagna, C., Verdier-Pinard, P., & Cleveland, D. W. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.12.003 · Cited by 729 · see citing works
Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver
Wang, B., Zhao, L., Fish, M., Logan, C. Y., & Nusse, R. (2015) · Nature · doi:10.1038/nature14863 · Cited by 674 · see citing works
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577 · see citing works
The ploidy conveyor of mature hepatocytes as a source of genetic variation
Duncan, A. W., Taylor, M. H., Hickey, R. D., Hanlon Newell, A. E., Lenzi, M. L., Olson, S. B., Finegold, M. J., & Grompe, M. (2010) · Nature · doi:10.1038/nature09414 · Cited by 525 · see citing works
Lee, J.-S., Chu, I.-S., Mikaelyan, A., Calvisi, D., Heo, J., Reddy, J., & Thorgeirsson, S. (2004) · Nature Genetics · doi:10.1038/ng1481 · Cited by 472 · see citing works
Polyploidy can drive rapid adaptation in yeast
Selmecki, A. M., Maruvka, Y. E., Richmond, P. A., Guillet, M., Noam Shoresh, F., Sorenson, A. L., De, S., Kishony, R., Franziska Michor, A., Dowell, R. D., et al. (2015) · Nature · doi:10.1038/nature14187 · Cited by 444 · see citing works
Diril, M. K., Ratnacaram, C. K., Padmakumar, V. C., Du, T., Wasser, M., Coppola, V., Tessarollo, L., & Kaldis, P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115201109 · Cited by 385 · see citing works
Experimental mouse models for hepatocellular carcinoma research
Heindryckx, F., Colle, I., & van Vlierberghe, H. (2009) · International journal of experimental pathology (Print) · doi:10.1111/j.1365-2613.2009.00656.x · Cited by 383 · see citing works
Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation
Ganem, N. J., Cornils, H., Chiu, S.-Y., O’Rourke, K. P., Arnaud, J., Yimlamai, D., Théry, M., Camargo, F. D., & Pellman, D. S. (2014) · Cell · doi:10.1016/j.cell.2014.06.029 · Cited by 375 · see citing works
Polyploids Exhibit Higher Potassium Uptake and Salinity Tolerance in Arabidopsis
Chao, D.-Y., Dilkes, B. P., Luo, H.-B., Douglas, A., Yakubova, E., Lahner, B., & Salt, D. (2013) · Science · doi:10.1126/science.1240561 · Cited by 333 · see citing works
The mutational landscapes of genetic and chemical models of Kras-driven lung cancer
Westcott, P. M. K., Halliwill, K. D., To, M. D., Rashid, M., Rust, A. G., Keane, T., Delrosario, R., Jen, K., Gurley, K. E., Kemp, C. J., et al. (2014) · Nature · doi:10.1038/nature13898 · Cited by 333 · see citing works
Colnot, S., Decaens, T., Niwa‐Kawakita, M., Godard, C., Hamard, G., Kahn, A., Giovannini, M., & Perret, C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404761101 · Cited by 326 · see citing works
Single cell sequencing reveals low levels of aneuploidy across mammalian tissues
Knouse, K. A., Wu, J., Whittaker, C. A., & Amon, A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1415287111 · Cited by 314 · see citing works
Zhu, H., Shah, S. P., Shyh‐Chang, N., Shinoda, G., Einhorn, W. S., Viswanathan, S. R., Takeuchi, A., Grasemann, C., Rinn, J. L., Lopez, M. F., et al. (2010) · Nature Genetics · doi:10.1038/ng.593 · Cited by 306 · see citing works
Self-citationGenome-scale RNAi profiling of cell division in human tissue culture cells
Kittler, R., Pelletier, L., Heninger, A., Slabicki, M. M., Theis, M., Mirosław, Ł., Poser, I., Lawo, S., Grabner, H., Kozak, K., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1659 · Cited by 299 · see citing works
Arid1a Has Context-Dependent Oncogenic and Tumor Suppressor Functions in Liver Cancer
Sun, X., Wang, S. C., Wei, Y., Luo, X., Jia, Y., Li, L., Gopal, P., Zhu, M., Nassour, I., Chuang, J.-C., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.10.007 · Cited by 257 · see citing works
Self-citationChromosome missegregation rate predicts whether aneuploidy will promote or suppress tumors
Silk, A. D., Zasadil, L. M., Holland, A., Vitre, B., Cleveland, D., & Weaver, B. A. (2013) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1317042110 · Cited by 256 · see citing works
Schaub, J. R., Malato, Y., Gormond, C., & Willenbring, H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.003 · Cited by 254 · see citing works
Davoli, T., & de Lange, T. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.044 · Cited by 242 · see citing works
Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease
Gentric, G., Maillet, V., Paradis, V., Couton, D., L’Hermitte, A., Panasyuk, G., Fromenty, B., Celton-Morizur, S., & Desdouets, C. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73957 · Cited by 240 · see citing works
LOSS OF P130 ACCELERATES TUMOR DEVELOPMENT IN A MOUSE MODEL FOR HUMAN SMALL CELL LUNG CARCINOMA
Schaffer, B. E., Park, K.-S., Yiu, G., Conklin, J. F., Lin, C., Burkhart, D. L., Karnezis, A., Sweet-Cordero, A., & Sage, J. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4228 · Cited by 235 · see citing works
Cancer vulnerabilities unveiled by genomic loss
Nijhawan, D., Zack, T., Ren, Y., Strickland, M., Lamothe, R., Schumacher, S., Tsherniak, A., Besche, H. C., Rosenbluh, J., Shehata, S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.07.023 · Cited by 224 · see citing works
Single-chromosome Gains Commonly Function as Tumor Suppressors
Sheltzer, J. M., Ko, J. H., Replogle, J. M., Habibe Burgos, N. C., Chung, E. S., Meehl, C. M., Sayles, N. M., Passerini, V., Storchova, Z., & Amon, A. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.12.004 · Cited by 201 · see citing works
Keng, V., Villanueva, A., Chiang, D. Y., Dupuy, A., Ryan, B. J., Matīse, I., Silverstein, K. A. T., Sarver, A., Starr, T., Akagi, K., et al. (2009) · Nature Biotechnology · doi:10.1038/nbt.1526 · Cited by 198 · see citing works
Frequent Aneuploidy Among Normal Human Hepatocytes
Duncan, A. W., Hanlon Newell, A. E., Smith, L., Wilson, E. M., Olson, S. B., Thayer, M. J., Strom, S. C., & Grompe, M. (2012) · Gastroenterology · doi:10.1053/j.gastro.2011.10.029 · Cited by 197 · see citing works
Polyploidization in Liver Tissue
Gentric, G., & Desdouets, C. (2014) · The American Journal of Pathology · doi:10.1016/j.ajpath.2013.06.035 · Cited by 192 · see citing works
Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets
Wang, Z., Li, Z., Ye, Y., Xie, L., & Li, W. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/7891574 · Cited by 191 · see citing works
Ben-David, U., Arad, G., Weissbein, U., Mandefro, B., Maimon, A., Golan-lev, T., Narwani, K., Clark, A., Andrews, P., Benvenisty, N., et al. (2014) · Nature Communications · doi:10.1038/ncomms5825 · Cited by 189 · see citing works
Zhou, K., Nguyen, L. H., Miller, J. B., Yan, Y., Kós, P., Xiong, H., Li, L., Hao, J., Minnig, J. T., Zhu, H., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1520756113 · Cited by 184 · see citing works
Self-citationAneuploidy, polyploidy and ploidy reversal in the liver.
Duncan, A. (2013) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.01.003 · Cited by 172 · see citing works
Liver tetraploidization is controlled by a new process of incomplete cytokinesis
Margall-Ducos, G., Celton-Morizur, S., Couton, D., Brégerie, O., & Desdouets, C. (2007) · Journal of Cell Science · doi:10.1242/jcs.016907 · Cited by 170 · see citing works
E2F8 is essential for polyploidization in mammalian cells
Pandit, S. K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C. J., Cornelissen, P. W. A., Toussaint, M. J. M., Lamers, W. H., & de Bruin, A. (2012) · Nature Cell Biology · doi:10.1038/ncb2585 · Cited by 168 · see citing works
Canonical and atypical E2Fs regulate the mammalian endocycle
Chen, H.-Z., Ouseph, M. M., Li, J., Pécot, T., Chokshi, V., Kent, L., Bae, S., Byrne, M., Duran, C., Comstock, G., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2595 · Cited by 161 · see citing works
Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2
Zhang, S.-H., Chen, Q.-H., Liu, Q., Li, Y., Sun, X.-F., Hong, L.-X., Ji, S., Liu, C.-Y., Geng, J., Zhang, W., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.04.004 · Cited by 155 · see citing works
Self-citationCelton-Morizur, S., Merlen, G., Couton, D., Margall-Ducos, G., & Desdouets, C. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38677 · Cited by 145 · see citing works
Dessı̀, S., Batetta, B., Pulisci, D., Spano, O., Anchisi, C., Tessitore, L., Costelli, P., Baccino, F. M., Aroasio, E., & Pani, P. (1994) · Cancer · doi:10.1002/1097-0142(19940115)73:2 · Cited by 137 · see citing works
Lack of intratumoral heterogeneity in DNA ploidy pattern of hepatocellular carcinoma.
Nagasue, N., Kohno, H., Hayashi, T., Yamanoi, A., Uchida, M., Takemoto, Y., Makino, Y., Ono, T., Hayashi, J., & Nakamura, T. (1993) · Gastroenterology · doi:10.1016/0016-5085(93)90150-b · Cited by 134 · see citing works
Bard-Chapeau, E. A., Nguyen, A.-T., Rust, A. G., Sayadi, A., Lee, P., Chua, B. Q., New, L., de Jong, J., Ward, J. M., Yew, C. C. K., et al. (2013) · Nature Genetics · doi:10.1038/ng.2847 · Cited by 117 · see citing works
Zhang, S., Nguyen, L. H., Zhou, K., Tu, H.-C., Sehgal, A., Nassour, I., Li, L., Gopal, P., Goodman, J. H., Singal, A. G., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.12.013 · Cited by 114 · see citing works
Self-citationChanges to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis
Toyoda, H., Bregerie, O., Vallet, A., Nalpas, B., Pivert, G., Brechot, C., & Desdouets, C. (2005) · Gut · doi:10.1136/gut.2004.043893 · Cited by 105 · see citing works
Liver-Specific pRB Loss Results in Ectopic Cell Cycle Entry and Aberrant Ploidy
Mayhew, C. N., Bosco, E. E., Fox, S. R., Okaya, T., Tarapore, P., Schwemberger, S. J., Babcock, G. F., Lentsch, A. B., Fukasawa, K., & Knudsen, E. S. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4221 · Cited by 101 · see citing works
E2f8 mediates tumor suppression in postnatal liver development
Kent, L. N., Rakijas, J. B., Pandit, S. K., Westendorp, B., Chen, H.-Z., Huntington, J. T., Tang, X., Bae, S., Srivastava, A., Senapati, S., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85506 · Cited by 95 · see citing works
p53 REGULATES A MITOTIC TRANSCRIPTION PROGRAM AND DETERMINES PLOIDY IN NORMAL MOUSE LIVER
Kurinna, S., Stratton, S., Coban, Z., Schumacher, J. M., Grompe, M., Duncan, A. W., & Barton, M. (2013) · Hepatology · doi:10.1002/hep.26233 · Cited by 92 · see citing works
Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis
Beer, S., Komatsubara, K., Bellovin, D., Kurobe, M., Sylvester, K., & Felsher, D. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002493 · Cited by 46
Mutations at codon 61 of the Ha‐ras proto‐oncogene in precancerous liver lesions of the B6C3F1 mouse
Buchmann, A., Mahr, J., Bauer‐Hofmann, R., & Schwarz, M. (1989) · Molecular Carcinogenesis · doi:10.1002/mc.2940020303 · Cited by 45
Oncogenic mutations and dysregulated pathways in obesity-associated hepatocellular carcinoma
Shen, J., Tsoi, H., Liang, Q., Chu, E., Liu, D.-B., Yu, C., Chan, T., Li, X., Sung, J. J. Y., Wong, V., et al. (2016) · Oncogene · doi:10.1038/onc.2016.162 · Cited by 39 · see citing works
Shoshani, O., Massalha, H., Shani, N., Kagan, S., Ravid, O., Madar, S., Trakhtenbrot, L., Leshkowitz, D., Rechavi, G., & Zipori, D. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1155 · Cited by 35 · see citing works
TALEN mediated somatic mutagenesis in murine models of cancer
Zhang, S.-Y., Li, L., Kendrick, S., Gerard, R., & Zhu, H. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0529 · Cited by 32 · see citing works
Self-citationβ‐Catenin (Ctnnb1) Gene Mutations in Diethylnitrosamine (DEN)‐induced Liver Tumors in Male F344 Rats
Yamada, Y., Yoshimi, N., Sugie, S., Suzui, M., Matsunaga, K., Kawabata, K., Hara, A., & Mori, H. (1999) · Japanese journal of cancer research : Gann · doi:10.1111/j.1349-7006.1999.tb00822.x · Cited by 28 · see citing works
The streaming liver IV: DNA content of the hepatocyte increases with its age
Schwartz‐Arad, D., Zajicek, G., & Bartfeld, E. (1989) · Liver International · doi:10.1111/j.1600-0676.1989.tb00385.x · Cited by 20 · see citing works
Caselitz, M., Masche, N., Bleck, J., Gebel, M., Atay, Z., Stern, C., Manns, M., & Kubicka, S. (2003) · Zeitschrift für Gastroenterologie - German Journal of Gastroenterology · doi:10.1055/s-2003-39637 · Cited by 10
Ingle (1991) · doi:10.1002/1097-0142(19910215)67:4
Flagged first, then by citations
2 of the 65 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
- Anti M Marra G Rapaccini GL Rumi C Bussa S Fadda G Vecchio FM Valenti A Percesepe A Pompili M 1994 DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy Cancer 73 281 288 8293389
- Fujimoto J Okamoto E Yamanaka N Toyosaka A Mitsunobu M 1991 Flow cytometric DNA analysis of hepatocellular carcinoma Cancer 67 939 944 1846770
- Premsrirut PK Dow LE Kim SY Camiolo M Malone CD Miething C Scuoppo C Zuber J Dickins RA Kogan SC 2011 A rapid and scalable system for studying gene function in mice using conditional RNA interference Cell 145 145 158 21458673 PMC3244080
- Tamura J Tanaka J Fujita K Yoshida M Kasamatsu T Arii S Tobe T 1992 Cell kinetics of regenerating liver after 70% hepatectomy in rats-2-color flow cytometric analysis HPB surgery: a world journal of hepatic, pancreatic and biliary surgery 5 103 114 discussion 114-105 PMC2442946 1610723
Cited by
Sorted by citations
Cheng, Q., Wei, T., Farbiak, L., Johnson, L. T., Dilliard, S. A., & Siegwart, D. J. (2020) · Nature Nanotechnology · doi:10.1038/s41565-020-0669-6 · Cited by 2,383 · see citing works
Self-citationThe broken cycle: E2F dysfunction in cancer
Kent, L. N., & Leone, G. W. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0143-7 · Cited by 786 · see citing works
Wei, T., Cheng, Q., Min, Y.-L., Olson, E. N., & Siegwart, D. J. (2020) · Nature Communications · doi:10.1038/s41467-020-17029-3 · Cited by 603 · see citing works
Self-citationMutations and mechanisms of WNT pathway tumour suppressors in cancer
Bugter, J. M., Fenderico, N., & Maurice, M. M. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-020-00307-z · Cited by 466 · see citing works
Cheng, Q., Wei, T., Jia, Y., Farbiak, L., Zhou, K., Zhang, S., Wei, Y., Zhu, H., & Siegwart, D. J. (2018) · Advanced Materials · doi:10.1002/adma.201805308 · Cited by 221 · see citing works
Self-citationPolyploidy: a biological force from cells to ecosystems
Fox, D. T., Soltis, D., Soltis, P., Ashman, T., & de Peer, Y. V. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.06.006 · Cited by 202 · see citing works
Polyploidy in liver development, homeostasis and disease
Donne, R., Saroul-Aïnama, M., Cordier, P., Celton-Morizur, S., & Desdouets, C. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0284-x · Cited by 188 · see citing works
Polyploidy in tissue homeostasis and regeneration
Øvrebø, J. I., & Edgar, B. A. (2018) · Development · doi:10.1242/dev.156034 · Cited by 171 · see citing works
“, 2018), as reported in hepatocytes (Zhang et al., 2018).”
The dualistic origin of human tumors
Liu, J. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.07.004 · Cited by 148 · see citing works
“PGCCs have been shown to inhibit tumor growth [97–99] and induce senescence [100,101], and polyploidy can suppress tumor formation in normal liver [102].”
BackgroundThe Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice
Wilkinson, P. D., Delgado, E. R., Alencastro, F., Leek, M. P., Roy, N., Weirich, M. P., Stahl, E. C., Otero, P. A., Chen, M. I., Brown, W. K., et al. (2019) · Hepatology · doi:10.1002/hep.30286 · Cited by 135 · see citing works
“, differentiation genes such as Albumin, forkhead box protein 3, and hepatocyte nuclear factor 4 alpha; cytochrome P450 family members; and cell-cycle genes).(10,16) To assess liver function following chronic injury, we maintained mice on a high-fat diet for 8 weeks.”
InfluentialMultiscale light-sheet organoid imaging framework
de Medeiros, G., Ortiz, R., Strnad, P., Boni, A., Moos, F., Repina, N. A., Meylan, L. C., Maurer, F., & Liberali, P. (2022) · Nature Communications · doi:10.1038/s41467-022-32465-z · Cited by 114 · see citing works
Zhang, S., Nguyen, L. H., Zhou, K., Tu, H.-C., Sehgal, A., Nassour, I., Li, L., Gopal, P., Goodman, J. H., Singal, A. G., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.12.013 · Cited by 114 · see citing works
Self-citationDerks, W. J. A., & Bergmann, O. (2020) · Circulation Research · doi:10.1161/circresaha.119.315408 · Cited by 188 · see citing works
Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer
Ge, J. Y., Shu, S., Kwon, M., Jovanović, B., Murphy, K. C., Gulvady, A. C., Fassl, A., Trinh, A. C., Kuang, Y., Heavey, G. A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16170-3 · Cited by 98 · see citing works
Lin, Y.-H., Zhang, S., Zhu, M., Lu, T., Chen, K., Wen, Z., Wang, S., Xiao, G., Luo, D., Jia, Y., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.026 · Cited by 91 · see citing works
Self-citationProliferative polyploid cells give rise to tumors via ploidy reduction
Matsumoto, T., Wakefield, L., Peters, A., Peto, M., Spellman, P., & Grompe, M. (2021) · Nature Communications · doi:10.1038/s41467-021-20916-y · Cited by 77 · see citing works
Cardiomyocyte Polyploidy and Implications for Heart Regeneration
Gan, P., Patterson, M., & Sucov, H. M. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034618 · Cited by 87 · see citing works
Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy
Richter, M. L., Deligiannis, I. K., Yin, K., Danese, A., Lleshi, E., Coupland, P., Vallejos, C. A., Matchett, K. P., Henderson, N. C., Colome-Tatche, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-24543-5 · Cited by 75 · see citing works
Wang, J., Batourina, E., Schneider, K., Souza, S. S., Swayne, T., Liu, C., George, C., Tate, T., Dan, H.-B., Wiessner, G., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.042 · Cited by 71 · see citing works
“On the other hand, recent studies suggest that polyploid hepatocytes suppress tumorigenesis compared to diploid hepatocytes (Zhang et al., 2018).”
Cohen, E., Allen, S. R., Sawyer, J. K., & Fox, D. T. (2018) · eLife · doi:10.7554/elife.38327 · Cited by 83 · see citing works
“V12}TL1 genetic reagent (D. melanogaster) UAS-hid, UAS-reaper Zhou et al 1997 antibody anti-Fasciclin III DSHB 7G10 antibody anti-Phospho-Histone H3 Cell Signaling ab9706 antibody anti-BrdU Serotec 3J9 antibody anti-Beta-Galactosidase Abcam ab9361 recombinant DNA reagent pUAST-FRT-Stop -FRT-rpr…”
InfluentialXiong, H., Liu, S., Wei, T., Cheng, Q., & Siegwart, D. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.06.030 · Cited by 64 · see citing works
Self-citationPolyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases
Anatskaya, O. V., & Vinogradov, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073542 · Cited by 61 · see citing works
“Others think that additional genomes are useful as they enhance cell function due to the acceleration of metabolic processes, protein synthesis, regenerative properties, and protect cells from oncogenic transformation [1,3,89,90].”
BackgroundImpact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics
Macı́as, R. I. R., Monte, M. J., Serrano, M. A., Santiago, J. M. G., Martin-Arribas, I., Simão, A. L., Castro, R. E., González‐Gallego, J., Mauriz, J. L., & Marı́n, J. J. G. (2021) · Aging · doi:10.18632/aging.203620 · Cited by 61 · see citing works
“increased copy numbers of tumor suppressor genes, such as p53, in polyploid cells [55].”
BackgroundPolyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury
Wilkinson, P. D., Alencastro, F., Delgado, E. R., Leek, M. P., Weirich, M. P., Otero, P. A., Roy, N., Brown, W. K., Oertel, M., & Duncan, A. W. (2019) · The American Journal of Pathology · doi:10.1016/j.ajpath.2019.02.008 · Cited by 60 · see citing works
“It has also been shown that livers deficient in E2f7 and/or E2f8 have increased susceptibility to spontaneous tumorigenesis and diethylnitrosamineinduced liver cancer.(24,25) Strikingly, hepatocytes from LKO mice are more proliferative in culture and during liver repopulation and partial hepatectomyeinduced regenerati…”
BackgroundSolving the polyploid mystery in health and disease
Gjelsvik, K. J., Besen-McNally, R., & Losick, V. P. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.10.005 · Cited by 59 · see citing works
“There may also be longterm detrimental consequences to switching from polyploidization to proliferative growth as mouse liver and Drosophila hindgut were found to be more sensitive to tumor growth upon oncogenic activation [22, 23, 54].”
BackgroundJia, Y., Li, L., Lin, Y.-H., Gopal, P., Shen, S., Zhou, K., Yu, X., Sharma, T., Zhang, Y., Siegwart, D. J., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.01.001 · Cited by 59 · see citing works
Self-citationSladky, V. C., Knapp, K., Soratroi, C., Heppke, J., Eichin, F., Rocamora-Reverte, L., Szabo, T., Bongiovanni, L., Westendorp, B., Moreno, E., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2019.12.016 · Cited by 55 · see citing works
“This has been ascribed to increased ploidy slowing down proliferative capacity of hepatocytes (Wilkinson et al., 2018) and generating a reservoir of tumor suppressors (Zhang et al., 2018b, 2018a).”
BackgroundInfluentialCancer regeneration: Polyploid cells are the key drivers of tumor progression.
Moein, S., Adibi, R., Meirelles, L. D. S., Nardi, N., & Gheisari, Y. (2020) · Biochimica et biophysica acta. Reviews on cancer · doi:10.1016/j.bbcan.2020.188408 · Cited by 53 · see citing works
Tetraploidy in cancer and its possible link to aging
Tanaka, K., Goto, H., Nishimura, Y., Kasahara, K., Mizoguchi, A., & Inagaki, M. (2018) · Cancer Science · doi:10.1111/cas.13717 · Cited by 54 · see citing works
Diploid hepatocytes drive physiological liver renewal in adult humansPreprint
Heinke, P., Rost, F., Rode, J., Welsch, T., Alkass, K., Feddema, J., Salehpour, M., Possnert, G., Druid, H., Brusch, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.07.230086 · Cited by 7 · see citing works
“This property has been questioned with regard to hepatocytes based on the results of several mouse studies that have described an equivalent proliferative capacity irrespective of their ploidy level (Duncan et al., 2010; Zhang et al., 2018).”
BackgroundResultHyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver
Lin, H., Huang, Y.-S., Fustin, J., Doi, M., Chen, H.-T., Lai, H.-H., Lin, S.-H., Lee, Y.-L., King, P.-C., Hou, H.-S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-20572-8 · Cited by 46 · see citing works
“5). tumor-suppressive role in the liver, but pathological hyperpoly-ploidy under stress conditions is a different situation 16 .”
Cellular origins of regenerating liver and hepatocellular carcinoma
Holczbauer, Á., Wangensteen, K. J., & Shin, S. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100416 · Cited by 39 · see citing works
“JHEP Reports 2022 loss of heterozygosity, while also being as susceptible to MYC oncogene activation as polyploid hepatocytes, in mouse models of altered hepatocyte ploidy status.(109) Furthermore, mouse strains with a higher percentage of polyploid hepatocytes”
BackgroundPIDDosome‐induced p53‐dependent ploidy restriction facilitates hepatocarcinogenesis
Sladky, V. C., Knapp, K., Szabo, T., Braun, V. Z., Bongiovanni, L., van den Bos, H., Spierings, D., Westendorp, B., Curinha, A., Stojaković, T., et al. (2020) · EMBO Reports · doi:10.15252/embr.202050893 · Cited by 43 · see citing works
“…contrast to these previous studies documenting protective effects of higher hepatocyte ploidy at the time of genotoxic challenge (Kent et al , 2016; Zhang et al , 2018a,b; Lin et al , 2020), deficiency in caspase-2, PIDD1 or RAIDD leads to ploidy increases long after DNA damage has occurred and…”
InfluentialLoss of hepatocyte cell division leads to liver inflammation and fibrosis
Dewhurst, M. R., Ow, J. R., Zafer, G., van Hul, N. K. M., Wollmann, H., Bisteau, X., Brough, D., Choi, H., & Kaldis, P. (2020) · PLOS Genetics · doi:10.1371/journal.pgen.1009084 · Cited by 42 · see citing works
“This happens physiologically downstream of the insulin signaling pathway [22] and may serve to protect against loss of tumor suppressors upon genomic aberrations induced by a nutrient-rich environment [23, 24].”
BackgroundPolyploidy control in hepatic health and disease
Sladky, V. C., Eichin, F., Reiberger, T., & Villunger, A. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.06.030 · Cited by 49 · see citing works
Li, L., Huang, K., Zhao, H., Chen, B., Ye, Q., & Yue, J. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1749471 · Cited by 49 · see citing works
“There is reported that Anln shRNA inhibits tumor suppressor but not oncogene by affecting the polyploidy in the liver [47].”
BackgroundSelf-citationGrendler, J., Lowgren, S., Mills, M. T., & Losick, V. P. (2018) · Development · doi:10.1242/dev.173005 · Cited by 40 · see citing works
Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation
Sladky, V. C., & Villunger, A. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-0556-6 · Cited by 39 · see citing works
The origins and functions of hepatic polyploidy
Zhang, S., Lin, Y.-H., Tarlow, B., & Zhu, H. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1618123 · Cited by 38 · see citing works
“To address the functionality of polyploidy in the liver, we built inducible tools to manipulate ploidy levels in vivo without permanent changes in genes [74].”
BackgroundMethodInfluentialSelf-citationWang, X., Yang, S.-A., Gong, S., Chang, C.-H., Portilla, J.-M., Chatterjee, D., Irianto, J., Bao, H., Huang, Y., & Deng, W. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.017 · Cited by 40 · see citing works
Whole-genome doubling in tissues and tumors
Vittoria, M. A., Quinton, R. J., & Ganem, N. J. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.08.004 · Cited by 43 · see citing works
Communal living: the role of polyploidy and syncytia in tissue biology
Peterson, N. G., & Fox, D. T. (2021) · Chromosome Research · doi:10.1007/s10577-021-09664-3 · Cited by 47 · see citing works
Katsuda, T., Hosaka, K., Matsuzaki, J., Usuba, W., Prieto‐Vila, M., Yamaguchi, T., Tsuchiya, A., Terai, S., & Ochiya, T. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.08.011 · Cited by 36 · see citing works
“On the other hand, the hepatocyte polyploidization prevents tumorigenesis by decreasing their susceptibility to genomic aberrations.(8,9) These reports suggested that ploidy status affects the phenotype of hepatocytes; however, the studies have been focused on specific processes.”
BackgroundMiller, J. B., & Siegwart, D. J. (2018) · Nano Research · doi:10.1007/s12274-018-2099-4 · Cited by 40 · see citing works
Self-citationLipid‐Modified Aminoglycosides for mRNA Delivery to the Liver
Yu, X., Liu, S., Cheng, Q., Wei, T., Lee, S. M., Zhang, D., & Siegwart, D. J. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.201901487 · Cited by 44 · see citing works
Self-citationSegeren, H. A., van Rijnberk, L. M., Moreno, E., Riemers, F., van Liere, E. V., Yuan, R.-X., Wubbolts, R., de Bruin, A., & Westendorp, B. (2020) · bioRxiv · doi:10.1101/2020.03.19.998674 · Cited by 32 · see citing works
Cardiac regenerative capacity: an evolutionary afterthought?
Nguyen, P. D., de Bakker, D. E. M., & Bakkers, J. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03831-9 · Cited by 34 · see citing works
Distinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30 · see citing works
Chiara, L. D., Conte, C., Antonelli, G., & Lazzeri, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011093 · Cited by 36 · see citing works
“Evolutionarily, polyploid/arrested PTC may represent a buff‐ ering mechanism to prevent tumor development [119].”
BackgroundChen, J., Li, Z., Jia, X., Song, W., Wu, H., Zhu, H., Xuan, Z., Du, Y., Zhu, X.-X., Song, G.-Y., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02274-1 · Cited by 29
“Previous study reported that ANLN was correlated with hepatocyte ploidy in mice [21].”
BackgroundInfluentialSelf-citationGamaev, L., Mizrahi, L., Friehmann, T., Rosenberg, N., Pappo, O., Olam, D., Zeira, E., Halpern, K. B., Caruso, S., Zucman-Rossi, J., et al. (2020) · Oncogene · doi:10.1038/s41388-020-01513-7 · Cited by 29 · see citing works
Chung, A. S., Mettlen, M., Ganguly, D., Lu, T., Wang, T., Brekken, R. A., Hsiehchen, D., & Zhu, H. (2020) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-20-0200 · Cited by 29 · see citing works
“Previous work from our laboratory and others has characterized the mutational landscape in DEN-induced tumors (45, 46), and our studies found recurrent mutations in several oncogenes and tumor suppressors (46).”
BackgroundSelf-citationWnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
Emerging role of E2F8 in human cancer
Lee, D. Y., Chun, J. N., Cho, M., So, I., & Jeon, J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166745 · Cited by 24 · see citing works
Differential roles for diploid and polyploid hepatocytes in acute and chronic liver injury
Wilkinson, P. D., & Duncan, A. (2020) · Seminars in liver disease (Print) · doi:10.1055/s-0040-1719175 · Cited by 25 · see citing works
Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases
Donné, R., Sangouard, F., Celton‐Morizur, S., & Desdouets, C. (2021) · Cancers · doi:10.3390/cancers13205151 · Cited by 28 · see citing works
“Diploid and polyploid livers were equally susceptible to oncogeneinduced carcinogenesis, but polyploid livers were more resistant to loss of heterozygosity (LOH) mechanisms mediating transformation [123].”
BackgroundResultXiao, J. X., Xu, W., Fei, X., Hao, F., Wang, N., Chen, Y.-J., & Wang, J.-Q. (2020) · Translational Oncology · doi:10.1016/j.tranon.2020.100815 · Cited by 23 · see citing works
“[21,22] suggested that the polyploid hepatocytes generated from cytokinesis failure could reduce HCC development in mouse models without adverse reactions including degeneration of either cell functions and liver regeneration.”
BackgroundWhite‐Gilbertson, S. J., Lü, P., Saatci, Ö., Şahin, Ö., Delaney, J. R., Öğretmen, B., & Voelkel‐Johnson, C. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107136 · Cited by 23 · see citing works
“Polyploidy, also known as whole genome duplication, has a protective effect in highly differentiated tissues such as the heart, liver, or muscle but is associated with poor prognosis in cancer due to increased genomic instability (1, 2).”
BackgroundCentriole signaling restricts hepatocyte ploidy to maintain liver integrityPreprint
Sladky, V. C., Akbari, H., Tapias-Gomez, D., Evans, L. T., Drown, C. G., Strong, M. A., LoMastro, G. M., Larman, T. C., & Holland, A. (2022) · Genes & Development · doi:10.1101/gad.349727.122 · Cited by 22 · see citing works
“In the context of hepatocarcinogenesis, a high degree of liver ploidy has been repeatedly shown to protect against transformation (Kent et al. 2016; Zhang et al. 2018a,b; Sladky et al. 2020a).”
Tavan, M., Azizi, A., Sarikhani, H., Mirjalili, M., & Rigano, M. (2022) · Scientia Horticulturae · doi:10.1016/j.scienta.2021.110592 · Cited by 22
Zhou, K., Johnson, L. T., Xiong, H., Barrios, S., Minnig, J. T., Yan, Y., Abram, B., Yu, X., & Siegwart, D. J. (2020) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.9b01288 · Cited by 23 · see citing works
Self-citationBroughton, K., Khieu, T., Nguyen, N., Rosa, M., Mohsin, S., Quijada, P. J., Wang, B.-Y. J., Echeagaray, O., Kubli, D. A., Kim, T., et al. (2019) · Communications Biology · doi:10.1038/s42003-019-0453-z · Cited by 22 · see citing works
Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers
Matsumoto, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169409 · Cited by 21 · see citing works
“Polyploidy is supposed to act as a “buffer” against genotoxic damage, particularly that attributed to the loss-offunction genetic alterations, because of redundant genetic alleles [39].”
BackgroundAmplified centrosomes—more than just a threat
Kiermaier, E., Stötzel, I., Schapfl, M. A., & Villunger, A. (2024) · EMBO Reports · doi:10.1038/s44319-024-00260-0 · Cited by 20 · see citing works
“Of note, ploidy does not seem to affect liver function, nor regenerative proliferation in mice, as documented by comparing mononucleated diploid livers or highly polyploid livers of wild-type animals (Pandit et al, 2012; Zhang et al, 2018; Lin et al, 2020).”
Pek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25 · see citing works
Functional consequences of somatic polyploidy in development
Darmasaputra, G., van Rijnberk, L. M., & Galli, M. (2024) · Development · doi:10.1242/dev.202392 · Cited by 31 · see citing works
“This cancer-protective function of polyploid hepatocytes has been attributed to the reduced chances of losing tumor suppressor genes in polyploid cells, as well as to reduced proliferative capacity of polyploid cells (Lin et al., 2020; Wilkinson et al., 2019; Zhang et al., 2018).”
Hepatocyte generation in liver homeostasis, repair, and regeneration
Pu, W., & Zhou, B. (2022) · Cell Regeneration · doi:10.1186/s13619-021-00101-8 · Cited by 25 · see citing works
Patterson, M., & Swift, S. K. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0193 · Cited by 19 · see citing works
“However, to the best of our knowledge, oxidative stress has not been tied to physiological polyploidy of hepatocytes, where research has instead indicated insulin/Akt signaling [10], E2f7 and E2f8 expression [9,56], and miR-122 [57].”
InfluentialCardiomyocyte nuclearity and ploidy: when is double trouble?
Landim-Vieira, M., Schipper, J. M., Pinto, J. R., & Chase, P. B. (2019) · Journal of Muscle Research and Cell Motility · doi:10.1007/s10974-019-09545-7 · Cited by 19 · see citing works
Patra, S., Naik, P. P., Mahapatra, K. K., Alotaibi, M. R., Patil, S., Patro, B. S., Sethi, G., Efferth, T., & Bhutia, S. K. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216843 · Cited by 20 · see citing works
Whole-Genome Doubling as a source of cancer: how, when, where, and why?
Sanz‐Gómez, N., González-Álvarez, M., Rivas, J. D. L., & de Cárcer, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1209136 · Cited by 23 · see citing works
“While in a diploid context, the inactivation of TSG leads to loss of heterozygosity (LOH) and the increasing likelihood of tumorigenesis, the extra TSG copies within a polyploid cell attenuate this probability, thus preventing tumorigenesis (Zhang et al., 2018).”
BackgroundInfluentialUnlocking Cardiomyocyte Renewal Potential for Myocardial Regeneration
Mehdipour, M., Park, S., & Huang, G. N. (2023) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2023.02.002 · Cited by 18 · see citing works
“This proposal has been supported by recent studies in hepatocytes [71].”
ResultNo Zones Left Behind: Democratic Hepatocytes Contribute to Liver Homeostasis and Repair
Monga, S. P. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2019.12.002 · Cited by 18 · see citing works
Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden
Hayashi, K., Horisaka, K., Harada, Y., Ogawa, Y., Yamashita, T., Kitano, T., Wakita, M., Fukusumi, T., Inohara, H., Hara, E., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02206-w · Cited by 24 · see citing works
“The buffering of genomic damage by polyploidy would be highly advantageous, especially in the liver [29], which is at high risk of exposure to genotoxic molecules.”
BackgroundContext-dependent effects of whole-genome duplication during mammary tumor recurrence
Newcomb, R., Dean, E., McKinney, B. J., & Alvarez, J. V. (2021) · Scientific Reports · doi:10.1038/s41598-021-94332-z · Cited by 16 · see citing works
“Extra copies of tumor suppressors have been shown to mediate the tumor suppressive effects of polyploidy in mouse models of liver cancer [36].”
BackgroundPolyploidisation pleiotropically buffers ageing in hepatocytes
Yin, K., Büttner, M., Deligiannis, I. K., Strzelecki, M., Zhang, L., Talavera-López, C. N., Theis, F. J., Odom, D. T., & Martinez‐Jimenez, C. P. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.03.043 · Cited by 13 · see citing works
“10,11,49,70,71 Here we have demonstrated the singular importance of polyploidy: in hepatocytes, tetraploid nuclei can act as a distinct cellular state that transcriptionally and genomically buffers phenotypic ageing.”
Sharma, S., Ghufran, S. M., Das, B., Roy, B., Ghose, S., & Biswas, S. (2021) · Life Science · doi:10.1016/j.lfs.2021.120119 · Cited by 15 · see citing works
Cellular polyploidy in organ homeostasis and regeneration
Fang, J.-T., de Bruin, A., Villunger, A., Schiffelers, R., Lei, Z., & Sluijter, J. (2022) · Protein & Cell · doi:10.1093/procel/pwac064 · Cited by 14 · see citing works
“…genome copies can prevent the unfavorable consequence of mutations and DNA damage, especially in some key genes, such as tumor suppressor genes (Zhang et al., 2018a), thereby improving cellular responsiveness and cell survival in response to stress (Anatskaya and Vinogradov, 2007; Mehrotra et…”
The role of Lamin B2 in human diseases.
Li, Y., Zhu, J., Yu, Z.-Y., Li, H., & Jin, X.-F. (2023) · Gene · doi:10.1016/j.gene.2023.147423 · Cited by 13 · see citing works
Wound-induced polyploidization is dependent on Integrin-Yki signaling
Besen-McNally, R., Gjelsvik, K. J., & Losick, V. P. (2020) · Biology Open · doi:10.1242/bio.055996 · Cited by 13 · see citing works
Hsieh, M.-H., Wei, Y.-L., Li, L., Nguyen, L. H., Lin, Y.-H., Yong, J. M., Sun, X.-X., Wang, X., Luo, X.-Y., Knutson, S. K., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci165734 · Cited by 12 · see citing works
“Sequencing of 242 of the most commonly mutated genes in human and murine HCCs in 50 individual DEN tumors (33) identified recurrent, mutually exclusive mutations in Egfr (Phe254Ile), Hras (Gln61Arg), and Braf (Val637Glu).”
Self-citationBinucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
Darmasaputra, G. S., Geerlings, C. C., Lopes, S. M. C. D. S., Clevers, H., & Galli, M. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202403020 · Cited by 12 · see citing works
The fate of extra centrosomes in newly formed tetraploid cells: should I stay, or should I go?
Bloomfield, M., & Cimini, D. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1210983 · Cited by 16 · see citing works
“Most evidence suggests that in this context, tetraploidy plays a tumor suppressive role in the liver by buffering the effects of harmful mutations (Zhang et al., 2018a; Zhang et al., 2018b; Lin et al., 2020; Wang et al., 2021).”
BackgroundCellular Senescence, a Novel Area of Investigation for Metastatic Diseases
Faggioli, F., Velarde, M. C., & Wiley, C. D. (2023) · Cells · doi:10.3390/cells12060860 · Cited by 15 · see citing works
CHRONOCRISIS: When Cell Cycle Asynchrony Generates DNA Damage in Polyploid Cells
Gemble, S., & Basto, R. (2020) · Bioessays · doi:10.1002/bies.202000105 · Cited by 12 · see citing works
Bu, W., Sun, X. F., Xue, X., Geng, S., Yang, T., Zhang, J., Li, Y., Feng, C., Liu, Q., Zhang, X., et al. (2024) · Hepatology · doi:10.1097/hep.0000000000000821 · Cited by 16 · see citing works
“[34] We showed here that while the polyploid hepatocytes caused by RAD51 deletion were indeed protected from DEN/CCl 4 -induced HCC, the protection was more likely due to the downregulation of P450 family genes that metabolize DEN and CCl 4 rather than the polyploid state.”
The Ploidy State as a Determinant of Hepatocyte Proliferation
Wilson, S. R., & Duncan, A. W. (2023) · Seminars in liver disease (Print) · doi:10.1055/a-2211-2144 · Cited by 11 · see citing works
“71 The signi fi cance of ploidy in HCC progression and its implications for prognosis warrants further investigation.”
BackgroundThe Controversial Role of Polyploidy in Hepatocellular Carcinoma
Wang, N., Hao, F., Shi, Y., & Wang, J.-Q. (2021) · OncoTargets and Therapy · doi:10.2147/ott.s340435 · Cited by 11 · see citing works
“as for rodents, polyploid hepatocytes appears around weaning (postnatal day 14 [P14] to P21) and increases with age.(4,10) In the liver, hepatocytes vary considerably in cell and nuclear size, number of nuclei per cell and DNA content per nucleus.”
BackgroundHepatic zonation determines tumorigenic potential of mutant β-catenin
Raven, A., Gilroy, K. L., Jin, H., Waldron, J. A., Leslie, H., Munro, J., Hall, H., Ridgway, R. A., Ford, C. A., Gulhan, D., et al. (2025) · Nature · doi:10.1038/s41586-025-09733-1 · Cited by 10 · see citing works
Self-citationLin, C., Kuzmanović, A., Wang, N., Liao, L., Ernst, S., Penners, C., Jans, A., Hammoor, T., Stach, P. B., Peltzer, M., et al. (2025) · Advanced Science · doi:10.1002/advs.202409729 · Cited by 7 · see citing works
Ploidy dynamics increase the risk of liver cancer initiation
Müller, M., May, S., & Bird, T. G. (2021) · Nature Communications · doi:10.1038/s41467-021-21897-8 · Cited by 10 · see citing works
Spindle Checkpoint Regulators in Insulin Signaling
Choi, E., & Yu, H.-T. (2018) · Front. Cell Dev. Biol. · doi:10.3389/fcell.2018.00161 · Cited by 10 · see citing works
Sharma, S. K., Ghufran, S. M., Aftab, M., Bihari, C., Ghose, S., & Biswas, S. (2024) · Journal of Cell Communication and Signaling · doi:10.1002/ccs3.12015 · Cited by 8 · see citing works
“29 However, the role of survivin in chronically injured liver and fibrosis is largely unknown.”
BackgroundThe endocycle restores tissue tension in the Drosophila abdomen post wound repair
Losick, V. P., & Duhaime, L. G. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109827 · Cited by 15 · see citing works
“In the liver, polyploidy can make hepatocytes more resistant to tumor growth by reducing proliferation (Wilkinson et al., 2019; Zhang et al., 2018).”
A Drosophila Model to Study Wound-induced Polyploidization
Bailey, E. C., Dehn, A. S., Gjelsvik, K. J., Besen-McNally, R., & Losick, V. P. (2020) · Journal of Visualized Experiments · doi:10.3791/61252 · Cited by 12 · see citing works
Signal control during tissue regeneration in adult animals
Bangru, S., Diegmiller, R., Talia, S. D., & Poss, K. D. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00917-1 · Cited by 10 · see citing works
Nakamura, K., Ishii, Y., Takasu, S., Nohmi, T., Shibutani, M., & Ogawa, K. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03099-9 · Cited by 8 · see citing works
Nacα protects the larval fat body from cell death by maintaining cellular proteostasis in Drosophila
Yamada, T., Yoshinari, Y., Tobo, M., Habara, O., & Nishimura, T. (2023) · Nature Communications · doi:10.1038/s41467-023-41103-1 · Cited by 7 · see citing works
Cyclin E overexpression in the Drosophila accessory gland induces tissue dysplasia
Molano-Fernández, M., Hickson, I., & Herranz, H. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.992253 · Cited by 7 · see citing works
“Endocycling cells typically block the mitotic program, and polyploidy can act as a tumor suppressor mechanism (Zhang et al., 2018).”
BackgroundA Role for Ploidy in Heart Regeneration
Kadow, Z. A., & Martin, J. F. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.02.004 · Cited by 7 · see citing works
“In another paper in this issue of Developmental Cell, Zhang et al. (2018) present strong evidence that polyploidy is not regulating the regenerative potential of the liver, but instead is important for tu-”
BackgroundInfluential
- Authors
- Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.-C., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., Siegwart, D. J., & Zhu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Zhu, Hao
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 44
- Issue
- 4
- Pages
- 447-459.e5
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC5828993
- OpenAlex
- W2626298693
- Cited by
- 180
- References
- 65
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 16 · 2023: 19 · 2022: 20 · 2021: 30 · 2020: 37 · 2019: 16 · 2018: 12 · 2017: 1
- FWCI
- 14.88
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-11-05)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (R1212, RP150596)
- Welch Foundation (I-1855)
- American Cancer Society (RSG-17-012-01, IRG-02-196)
- Pollack Foundation
- NIH/NCI (R01CA190525)
- CPRIT Individual Investigator Award (RP170267)
- CPRIT Early Translation Award (DP150077)
- Stand Up To Cancer Innovative Research Grant (SU2C-AACR-IRG 10-16)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- polyploidy, liver, hepatocytes, tumor suppression, endoreduplication, cytokinesis failure, early weaning, E2F8, anillin, hepatocarcinogenesis, MYC oncogene, Cas9, high-fat diet, liver regeneration, liver injury
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Female, Liver, Liver Neoplasms, Experimental, Liver Regeneration, Male, Mice, Inbred BALB C, Mice, Inbred C3H, Microfilament Proteins, Polyploidy, Repressor Proteins, Mice, Knockout, Hepatocytes, Cytokinesis, Mice
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