{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T08:12:30Z","timestamp":1773648750040,"version":"3.50.1"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:00:00Z","timestamp":1768348800000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and objectives<\/jats:title>\n                    <jats:p>Life history enlightened therapies (LHETs) were originally developed in cancer to combat therapeutic resistance by targeting pathological cell state transitions that enable evolutionary rescue and adaptation to therapy. In this paper, we expand the scope of LHETs to cancer prevention, namely, metabolic dysfunction-associated steatohepatitis (MASH)-induced hepatocellular carcinoma (HCC) initiation. We focus on endocycling, a process wherein cells undergo whole-genome duplication via mitotic skipping, as a keystone life history transition that promotes HCC initiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>A key obstacle to LHET translation is the lack of systematic methods that capture cellular life histories and their molecular drivers. To address this gap, we introduce cell cycle mapping, a technique that integrates in situ multiplexed immunofluorescence imaging with manifold learning to visualize the life history of proliferating cells and proteins involved in transitions to pathological cell states.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Mathematical modeling demonstrated how endocycling can create an environment that promotes HCC initiation and revealed the potential for endocycle-targeting therapies to prevent HCC. Using cell cycle mapping on human MASH liver tissues, we identified the molecular factors that drive pathological endocycling (Wee1, CDK2, and RAIDD), providing new therapeutic targets for pre-clinical investigation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and implications<\/jats:title>\n                    <jats:p>This application illustrates how cell cycle mapping can uncover key proteins that drive disease-associated cell state transitions and broaden the scope of LHETs from therapy resistance to cancer prevention. More broadly, our study establishes a generalizable pipeline for inferring the life history of cells in diseased tissues and potential interventions for disease management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/emph\/eoag002","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T12:18:47Z","timestamp":1768220327000},"page":"1-13","source":"Crossref","is-referenced-by-count":0,"title":["Life history enlightened therapies: cell cycle mapping to identify molecular targets to prevent hepatocellular carcinoma"],"prefix":"10.1093","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-626X","authenticated-orcid":false,"given":"Anuraag","family":"Bukkuri","sequence":"first","affiliation":[{"name":"Department of Computational and Systems Biology, Hillman Cancer Center, Center for Evolutionary Biology and Medicine, University of Pittsburgh , Pittsburgh, PA ,","place":["USA"]},{"name":"Department of Mathematics , City St George\u2019s, University of London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janet","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Hillman Cancer Center, Center for Evolutionary Biology and Medicine, University of Pittsburgh , Pittsburgh, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew W","family":"Duncan","sequence":"additional","affiliation":[{"name":"Department of Pathology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh \u00a0 School of Medicine, University of Pittsburgh, Pittsburgh, PA ,","place":["USA"]},{"name":"Department of Bioengineering, School of Engineering, University of Pittsburgh , Pittsburgh, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Stallaert","sequence":"additional","affiliation":[{"name":"Department of Computational and Systems Biology, Hillman Cancer Center, Center for Evolutionary Biology and Medicine, University of Pittsburgh , Pittsburgh, PA ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"2026031603362428200_ref1","volume-title":"The Evolution of Life Histories","author":"Stearns","year":"1992","edition":"1st"},{"key":"2026031603362428200_ref2","volume-title":"The Evolution of Life Histories; Theory and Analysis","author":"Roff","year":"1993"},{"key":"2026031603362428200_ref3","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.2307\/1939225","article-title":"A stage-based population model for loggerhead sea turtles and implications for conservation","volume":"68","author":"Crouse","year":"1987","journal-title":"Ecology."},{"key":"2026031603362428200_ref4","volume-title":"Decline of the Sea Turtles: Causes and Prevention","author":"Committee on Sea Turtle Conservation","year":"1990"},{"key":"2026031603362428200_ref5","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-42368-8","article-title":"A mathematical investigation of polyaneuploid cancer cell memory and cross-resistance in state-structured cancer populations","volume":"13","author":"Bukkuri","year":"2023","journal-title":"Sci Rep"},{"key":"2026031603362428200_ref6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-022-17456-w","article-title":"Stochastic models of mendelian and reverse transcriptional inheritance in state-structured cancer populations","volume":"12","author":"Bukkuri","year":"2022","journal-title":"Sci Rep"},{"key":"2026031603362428200_ref7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-022-18137-4","article-title":"A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells","volume":"12","author":"Bukkuri","year":"2022","journal-title":"Sci Rep"},{"key":"2026031603362428200_ref8","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1158\/2767-9764.CRC-23-0396","article-title":"Drug-resilient cancer cell phenotype is acquired via polyploidization associated with early stress response coupled to HIF2\u03b1 transcriptional regulation","volume":"4","author":"Carroll","year":"2024","journal-title":"Cancer Research Communications"},{"key":"2026031603362428200_ref9","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1016\/j.cels.2021.10.007","article-title":"The structure of the human cell cycle","volume":"13","author":"Stallaert","year":"2022","journal-title":"Cell Syst"},{"key":"2026031603362428200_ref10","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202211087","article-title":"The molecular architecture of cell cycle arrest","volume":"18","author":"Stallaert","year":"2022","journal-title":"Mol Syst Biol"},{"key":"2026031603362428200_ref11","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1002\/1878-0261.13685","article-title":"MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives","volume":"19","author":"Karin","year":"2025","journal-title":"Mol Oncol"},{"key":"2026031603362428200_ref12","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1097\/HEP.0000000000000786","article-title":"Molecular mechanisms in MASLD\/MASH-related HCC","volume":"82","author":"Wang","year":"2024","journal-title":"Hepatology."},{"key":"2026031603362428200_ref13","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.cgh.2018.05.057","article-title":"Nonalcoholic steatohepatitis is the fastest growing cause of hepatocellular carcinoma in liver transplant candidates","volume":"17","author":"Younossi","year":"2019","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2026031603362428200_ref14","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.cgh.2023.05.019","article-title":"NASH is the leading cause of hepatocellular carcinoma in liver transplant candidates","volume":"22","author":"Koh","year":"2024","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2026031603362428200_ref15","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1016\/j.cmet.2022.05.003","article-title":"Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer","volume":"34","author":"Huang","year":"2022","journal-title":"Cell Metab"},{"key":"2026031603362428200_ref16","doi-asserted-by":"publisher","first-page":"391","DOI":"10.4062\/biomolther.2022.070","article-title":"Polyploidization of hepatocytes: insights into the pathogenesis of liver diseases","volume":"30","author":"Kim","year":"2022","journal-title":"Biomol Ther (Seoul)"},{"key":"2026031603362428200_ref17","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1002\/hep.27908","article-title":"Pathological polyploidy in liver disease","volume":"62","author":"Hsu","year":"2015","journal-title":"Hepatology."},{"key":"2026031603362428200_ref18","doi-asserted-by":"publisher","first-page":"C849","DOI":"10.1152\/ajpcell.00081.2023","article-title":"Polyploid tubular cells initiate a TGF-\u03b21 controlled loop that sustains polyploidization and fibrosis after acute kidney injury","volume":"325","author":"De Chiara","year":"2023","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026031603362428200_ref19","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.kint.2023.10.036","article-title":"Polyploid tubular cells: a shortcut to stress adaptation","volume":"105","author":"De Chiara","year":"2024","journal-title":"Kidney Int"},{"key":"2026031603362428200_ref20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33110-5","article-title":"Tubular cell polyploidy protects from lethal acute kidney injury but promotes consequent chronic kidney disease","volume":"13","author":"De Chiara","year":"2022","journal-title":"Nat Commun"},{"key":"2026031603362428200_ref21","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/s41575-020-0284-x","article-title":"Polyploidy in liver development, homeostasis and disease","volume":"17","author":"Donne","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2026031603362428200_ref22","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1172\/JCI73957","article-title":"Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease","volume":"125","author":"Gentric","year":"2015","journal-title":"J Clin Invest"},{"key":"2026031603362428200_ref23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1009084","article-title":"Loss of hepatocyte cell division leads to liver inflammation and fibrosis","volume":"16","author":"Dewhurst","year":"2020","journal-title":"PLoS Genet"},{"key":"2026031603362428200_ref24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052238","article-title":"Immunomodulation by inflammation during liver and gastrointestinal tumorigenesis and aging","volume":"22","author":"Nagai","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026031603362428200_ref25","doi-asserted-by":"publisher","first-page":"026","DOI":"10.1055\/s-0038-1676806","article-title":"Inflammation and liver cancer: molecular mechanisms and therapeutic targets","volume":"39","author":"Yang","year":"2019","journal-title":"Semin Liver Dis"},{"key":"2026031603362428200_ref26","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/nrg1711","article-title":"The advantages and disadvantages of being polyploid","volume":"6","author":"Comai","year":"2005","journal-title":"Nat Rev Genet"},{"key":"2026031603362428200_ref27","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1242\/dev.098871","article-title":"Induction of endocycles represses apoptosis independently of differentiation and predisposes cells to genome instability","volume":"141","author":"Hassel","year":"2014","journal-title":"Development."},{"key":"2026031603362428200_ref28","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1101\/gad.1829209","article-title":"Endoreplication: polyploidy with purpose","volume":"23","author":"Lee","year":"2009","journal-title":"Genes Dev"},{"key":"2026031603362428200_ref29","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.canlet.2021.05.007","article-title":"Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation","volume":"513","author":"Yun","year":"2021","journal-title":"Cancer Lett"},{"key":"2026031603362428200_ref30","doi-asserted-by":"publisher","first-page":"243\u201362","DOI":"10.1007\/978-1-0716-3557-5_15","article-title":"Cell cycle mapping using multiplexed immunofluorescence","volume":"2740","author":"Kedziora","year":"2024","journal-title":"Methods Mol Biol"},{"key":"2026031603362428200_ref31","doi-asserted-by":"publisher","first-page":"11982","DOI":"10.1073\/pnas.1300136110","article-title":"Highly multiplexed single-cell analysis of formalinfixed, paraffin-embedded cancer tissue","volume":"110","author":"Gerdes","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026031603362428200_ref32","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s41592-020-01018-x","article-title":"Cellpose: a generalist algorithm for cellular segmentation","volume":"18","author":"Stringer","year":"2021","journal-title":"Nat Methods"},{"key":"2026031603362428200_ref33","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1038\/s41587-019-0336-3","article-title":"Visualizing structure and transitions in high-dimensional biological data","volume":"37","author":"Moon","year":"2019","journal-title":"Nat Biotechnol"},{"key":"2026031603362428200_ref34","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s12064-023-00410-3","article-title":"Modeling stress-induced responses: plasticity in continuous state space and gradual clonal evolution","volume":"143","author":"Bukkuri","year":"2024","journal-title":"Theory Biosci"},{"key":"2026031603362428200_ref35","doi-asserted-by":"publisher","DOI":"10.1002\/ece3.10591","article-title":"The contribution of evolvability to the eco-evolutionary dynamics of competing species","volume":"13","author":"Bukkuri","year":"2023","journal-title":"Ecol Evol"},{"key":"2026031603362428200_ref36","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s12032-023-01968-0","article-title":"Modeling cancer\u2019s ecological and evolutionary dynamics","volume":"40","author":"Bukkuri","year":"2023","journal-title":"Med Oncol"},{"key":"2026031603362428200_ref37","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1158\/2159-8290.CD-24-0861","article-title":"The hallmarks of cancer as eco-evolutionary processes","volume":"15","author":"Bhattacharya","year":"2025","journal-title":"Cancer Discov"},{"key":"2026031603362428200_ref38","first-page":"1","article-title":"GLUT1 production in cancer cells: a tragedy of the commons","volume":"8","author":"Bukkuri","year":"2022","journal-title":"Nature Project Journal Systems Biology and Applications"},{"key":"2026031603362428200_ref39","doi-asserted-by":"publisher","DOI":"10.1186\/2041-9414-4-5","article-title":"Tumor hypoxia as a driving force in genetic instability","volume":"4","author":"Luoto","year":"2013","journal-title":"Genome Integr"},{"key":"2026031603362428200_ref40","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00781-9","article-title":"Tumour hypoxia in driving genomic instability and tumour evolution","volume":"25","author":"Suvac","year":"2025","journal-title":"Nat Rev Cancer"},{"key":"2026031603362428200_ref41","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.ccell.2017.11.015","article-title":"Inflammation, ROS, and mutagenesis","volume":"32","author":"El-Kenawi","year":"2017","journal-title":"Cancer Cell"},{"key":"2026031603362428200_ref42","doi-asserted-by":"publisher","first-page":"101084","DOI":"10.1016\/j.redox.2018.101084","article-title":"ROS and the DNA damage response in cancer","volume":"25","author":"Srinivas","year":"2019","journal-title":"Redox Biol"},{"key":"2026031603362428200_ref43","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1146\/annurev-physiol-021119-034627","article-title":"The acidic tumor microenvironment as a driver of cancer","volume":"82","author":"Boedtkjer","year":"2020","journal-title":"Annu Rev Physiol"},{"key":"2026031603362428200_ref44","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s10555-019-09787-4","article-title":"Acidosis and cancer: from mechanism to neutralization","volume":"38","author":"Ibrahim-Hashim","year":"2019","journal-title":"Cancer Metastasis Rev"},{"key":"2026031603362428200_ref45","doi-asserted-by":"publisher","first-page":"203964","DOI":"10.1016\/j.cdev.2024.203964","article-title":"Of criminals and cancer: the importance of social bonds and innate morality on cellular societies","volume":"180","author":"Bukkuri","year":"2024","journal-title":"Cells & Development"},{"key":"2026031603362428200_ref46","first-page":"1","article-title":"Mathematical modeling of field cancerization through the lens of cancer behavioral ecology","author":"Bukkuri","year":"2023"},{"key":"2026031603362428200_ref47","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3389\/fevo.2021.678533","article-title":"Viewing cancer through the lens of corruption: using behavioral ecology to understand cancer","volume":"9","author":"Bukkuri","year":"2021","journal-title":"Front Ecol Evol"},{"key":"2026031603362428200_ref48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004794","article-title":"Global assessment of schistosomiasis control over the past century shows targeting the snail intermediate host works best","volume":"10","author":"Sokolow","year":"2016","journal-title":"PLoS Negl Trop Dis"},{"key":"2026031603362428200_ref49","doi-asserted-by":"publisher","first-page":"9650","DOI":"10.1073\/pnas.1502651112","article-title":"Reduced transmission of human schistosomiasis after restoration of a native river prawn that preys on the snail intermediate host","volume":"112","author":"Sokolow","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026031603362428200_ref50","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/0035-9203(65)90152-5","article-title":"The dynamics of helminth infections, with special reference to schistosomes","volume":"59","author":"Macdonald","year":"1965","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"2026031603362428200_ref51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fevo.2021.676071","article-title":"Coupled source-sink habitats produce spatial and temporal variation of cancer cell molecular properties as an alternative to branched clonal evolution and stem cell paradigms","volume":"9","author":"Cunningham","year":"2021","journal-title":"Front Ecol Evol"},{"key":"2026031603362428200_ref52","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1038\/s41586-019-1670-9","article-title":"Somatic mutations and clonal dynamics in healthy and cirrhotic human liver","volume":"574","author":"Brunner","year":"2019","journal-title":"Nature."},{"key":"2026031603362428200_ref53","doi-asserted-by":"publisher","first-page":"39021","DOI":"10.1038\/s41598-025-24732-y","article-title":"Interrogating subclonal heterogeneity of liver cancer with single-cell multi-omics analysis","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci Rep"},{"key":"2026031603362428200_ref54","doi-asserted-by":"publisher","first-page":"48688","DOI":"10.18632\/oncotarget.16231","article-title":"Adverse genomic alterations and stemness features are induced by field cancerization in the microenvironment of hepatocellular carcinomas","volume":"8","author":"Castven","year":"2017","journal-title":"Oncotarget."},{"key":"2026031603362428200_ref55","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1016\/j.jhep.2021.09.014","article-title":"Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis","volume":"75","author":"Pinyol","year":"2021","journal-title":"J Hepatol"},{"key":"2026031603362428200_ref56","doi-asserted-by":"publisher","first-page":"6506","DOI":"10.1038\/s41467-024-50660-y","article-title":"A male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma","volume":"15","author":"Jeong","year":"2024","journal-title":"Nat Commun"},{"key":"2026031603362428200_ref57","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3694-7_5","article-title":"A mouse model of hepatocellular carcinoma induced by streptozotocin and high-fat diet","volume":"2769","author":"Moti\u00f1o","year":"2024","journal-title":"Methods Mol Biol"},{"key":"2026031603362428200_ref58","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1002\/hep.29914","article-title":"Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis","volume":"68","author":"Windt","year":"2018","journal-title":"Hepatology."},{"key":"2026031603362428200_ref59","first-page":"4849","article-title":"Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as a human stratification model in mice","volume":"34","author":"Takakura","year":"2014","journal-title":"Anticancer Res"},{"key":"2026031603362428200_ref60","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s00795-013-0016-1","article-title":"A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma","volume":"46","author":"Fujii","year":"2013","journal-title":"Med Mol Morphol"},{"key":"2026031603362428200_ref61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0158156","article-title":"Antifibrotic effects of the dual CCR2\/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis","volume":"11","author":"Lefebvre","year":"2016","journal-title":"PLoS One"},{"key":"2026031603362428200_ref62","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1002\/hep4.1368","article-title":"Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents","volume":"3","author":"Hernandez","year":"2019","journal-title":"Hepatol Commun"},{"key":"2026031603362428200_ref63","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32281-5","article-title":"Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo","volume":"13","author":"Ni","year":"2022","journal-title":"Nat Commun"},{"key":"2026031603362428200_ref64","doi-asserted-by":"publisher","first-page":"1640","DOI":"10.1016\/j.stem.2023.10.008","article-title":"VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis","volume":"30","author":"Rizvi","year":"2023","journal-title":"Cell Stem Cell"},{"key":"2026031603362428200_ref65","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.addr.2020.06.017","article-title":"Lipid-based nanoparticle technologies for liver targeting","volume":"154-155","author":"B\u00f6ttger","year":"2020","journal-title":"Adv Drug Deliv Rev"},{"key":"2026031603362428200_ref66","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1111\/eva.12929","article-title":"Poly-aneuploid cancer cells promote evolvability, generating lethal cancer","volume":"13","author":"Pienta","year":"2020","journal-title":"Evol Appl"},{"key":"2026031603362428200_ref67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1073\/pnas.2020838118","article-title":"Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells","volume":"118","author":"Pienta","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026031603362428200_ref68","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.semcancer.2020.11.016","article-title":"Cancer cells employ an evolutionarily conserved polyploidization program to resist therapy","volume":"81","author":"Pienta","year":"2020","journal-title":"Semin Cancer Biol"},{"key":"2026031603362428200_ref69","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1158\/1541-7786.MCR-19-1158","article-title":"Convergent evolution, evolving evolvability, and the origins of lethal cancer","volume":"18","author":"Pienta","year":"2020","journal-title":"Mol Cancer Res"},{"key":"2026031603362428200_ref70","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1002\/pros.23877","article-title":"Polyploid giant cancer cells: unrecognized actuators of tumorigenesis, metastasis, and resistance","volume":"79","author":"Amend","year":"2019","journal-title":"Prostate."},{"key":"2026031603362428200_ref71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1088\/2057-1739\/aa83bf","article-title":"Epithelial and mesenchymal prostate cancer cell population dynamics on a complex drug landscape","volume":"3","author":"Lin","year":"2017","journal-title":"Converg Sci Phys Oncol"},{"key":"2026031603362428200_ref72","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2174\/1381612821666141211120604","article-title":"Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance","volume":"21","author":"Luo","year":"2015","journal-title":"Curr Pharm Des"},{"key":"2026031603362428200_ref73","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s10585-019-09958-1","article-title":"The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells","volume":"36","author":"Lin","year":"2019","journal-title":"Clin Exp Metastasis"},{"key":"2026031603362428200_ref74","first-page":"1","article-title":"Nuclear morphology and functional characteristics that enable survival of cells in the polyaneuploid cancer cell state following cytotoxic chemotherapy","author":"Kim","year":"2022","journal-title":"bioRxiv."},{"key":"2026031603362428200_ref75","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s10585-023-10216-8","article-title":"Cells in the polyaneuploid cancer cell (PACC) state have increased metastatic potential","volume":"40","author":"Mallin","year":"2023","journal-title":"Clin Exp Metastasis"},{"key":"2026031603362428200_ref76","doi-asserted-by":"publisher","first-page":"100906","DOI":"10.1016\/j.neo.2023.100906","article-title":"Nuclear morphology predicts cell survival to cisplatin chemotherapy","volume":"42","author":"Kim","year":"2023","journal-title":"Neoplasia."},{"key":"2026031603362428200_ref77","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/pros.24459","article-title":"Presence of cells in the polyaneuploid cancer cell (PACC) state predicts the risk of recurrence in prostate cancer","volume":"83","author":"Trabzonlu","year":"2023","journal-title":"Prostate."},{"key":"2026031603362428200_ref78","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abi7964","article-title":"Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease","volume":"13","author":"Bischof","year":"2021","journal-title":"Sci Transl Med"},{"key":"2026031603362428200_ref79","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.kint.2022.07.003","article-title":"Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1","volume":"102","author":"Airik","year":"2022","journal-title":"Kidney Int"}],"container-title":["Evolution, Medicine, and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/emph\/advance-article-pdf\/doi\/10.1093\/emph\/eoag002\/66405039\/eoag002.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/emph\/article-pdf\/14\/1\/1\/66405039\/eoag002.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/emph\/article-pdf\/14\/1\/1\/66405039\/eoag002.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T07:36:31Z","timestamp":1773646591000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/emph\/article\/14\/1\/1\/8425002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":79,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,7]]}},"URL":"https:\/\/doi.org\/10.1093\/emph\/eoag002","relation":{},"ISSN":["2050-6201"],"issn-type":[{"value":"2050-6201","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]}}}