Education & Training
- BS, Biology, University of North Carolina at Chapel Hill, 1992
- PhD, Pharmacology; Cell & Molecular Biology, Duke University, 2005
- Postdoc, Oregon Health & Science University, Liver Biology, 2011
Research Interest Summary
Research in the Duncan lab focuses on liver development, homeostasis, and regeneration. Polyploidy is a defining feature of the adult liver. Hepatocytes are either mononucleate or binucleate, and ploidy is determined by the number of nuclei per cell as well as the ploidy of each nucleus. Although hepatic polyploidy has been described for well over 100 years, the functional role of hepatic polyploidization is unclear. Dr. Duncan's lab recently showed that regenerating polyploid hepatocytes undergo specialized cell divisions to form aneuploid daughter cells, generating genetic diversity within the liver. Moreover, in rodent models, chromosome-specific aneuploid hepatocytes were shown to play a specialized role in liver regeneration, promoting adaptation and resistance to different forms of chronic liver injury.
Specific projects involve the following areas. First, identification of the molecular and cellular players that regulate aneuploidy/polyploidy is ongoing. The cell cycle in most normal mammalian cells is tightly regulated, prohibiting the expansion of polyploid and/or aneuploid cells. Experiments examine the extent of hepatocyte-specific cell cycle regulation. Additionally, multiple types of cells coordinate the overall degree of polyploidy/aneuploidy in the liver. Studies are underway to determine how diverse cell types (including stem and progenitor cells) contribute to genetic diversity. Second, current work investigates the function of aneuploid hepatocytes. Although aneuploidy in the liver is exceptionally high (>50% of hepatocytes), spontaneous liver cancer is very rare, suggesting that aneuploidy is not necessarily a predisposition for liver cancer. Recent data suggest that hepatic aneuploidy is beneficial, promoting adaptation to liver injury. We are actively developing new mouse models to explore "beneficial" and "pathological" adaptation mediated by aneuploid hepatocytes. Finally, how polyploid and aneuploid hepatocytes affect human liver disease is unknown. Studies are underway to determine how these cells contribute to pathogenesis and/or regeneration in a variety of liver diseases, including hepatocellular carcinoma and alcohol liver disease.
Barajas JM, Lin CH, Sun HL, Alencastro F, Zhu AC, Aljuhani M, Navari L, Yilmaz SA, Yu L, Corps K, He C, Duncan AW*, Ghoshal G*. METTL3 Regulates Liver Homeostasis, Hepatocyte Ploidy, and Circadian Rhythm-Controlled Gene Expression in Mice. Am J Pathol. 2022;192(1):56-71. PubMed PMID: 34599880 (*Co-Senior authors)
Wilkinson PD, Duncan AW. Differential Roles for Diploid and Polyploid Hepatocytes in Acute and Chronic Liver Injury. Seminars in Liver Disease. 2021;41:42-9. PubMed PMID: 33764484.
Delgado ER*, Erickson HL*, Tao J, Monga SP, Duncan AW**, Anakk S**. Scaffolding Protein IQGAP1 is Dispensable But Its Overexpression Promotes Hepatocellular Carcinoma via YAP1 Signaling. Molecular and Cellular Biology. 2021;41(4). PubMed PMID: 33526450. (*Equal authors; **Co-Senior authors)
Stahl EC, Delgado ER, Alencastro F, LoPresti ST, Wilkinson PD, Roy N, Haschak MJ, Skillen CD, Monga SP, Duncan AW*, Brown BN*. Inflammation and Ectopic Fat Deposition in the Aging Murine Liver Is Influenced by CCR2. Am J Pathol. 2020;190(2):372-87. PubMed PMID: 31843499. (*Co-Senior authors).
Wilkinson PD, Alencastro F, Delgado ER, Leek MP, Weirich MP, Otero PA, Roy N, Brown WK, Oertel M, Duncan AW. Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury. Am J Pathol. 2019;189(6):1241-55. PubMed PMID: 30928253.
Wilkinson PD, Delgado ER, Alencastro F, Leek MP, Roy N, Weirich MP, Stahl EC, Otero PA, Chen MI, Brown WK, Duncan AW. The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice. Hepatology. 2019;69(3):1242-58. PubMed PMID: 30244478.
Hsu SH*, Delgado ER*, Otero PA, Teng KY, Kutay H, Meehan KM, Moroney JB, Monga JK, Hand NJ, Friedman JR, Ghoshal K, Duncan AW. MicroRNA-122 Regulates Polyploidization in the Murine Liver. Hepatology. 2016;64(2):599-615. PubMed PMID: 27016325. (*Equal authors)
Duncan AW†, Hanlon Newell AE, Bi W, Finegold MJ, Olson SB, Beaudet AL, Grompe M. Aneuploidy as a mechanism for stress-induced liver adaptation. The Journal of clinical investigation. 2012;122(9):3307-15. PubMed PMID: 22863619. (†Corresponding author)
Duncan AW†, Hanlon Newell AE, Smith L, Wilson EM, Olson SB, Thayer MJ, Strom SC, Grompe M. Frequent aneuploidy among normal human hepatocytes. Gastroenterology. 2012;142(1):25-8. PubMed PMID: 22057114. (†Corresponding author)
Duncan AW†, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB, Finegold MJ, Grompe M. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature. 2010;467(7316):707-10. PubMed PMID: 20861837. (†Corresponding author)