Semin Liver Dis 2023; 43(04): 472-484
DOI: 10.1055/a-2207-9834
Review Article

Biliary Tract Cancer: Molecular Biology of Precursor Lesions

Fátima Manzano-Núñez
1   de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Lara Prates Tiago Aguilar
1   de Duve Institute, Université catholique de Louvain, Brussels, Belgium
Christine Sempoux
2   Institute of Pathology, Lausanne University Hospital CHUV, University of Lausanne, Lausanne, Switzerland
Frédéric P. Lemaigre
1   de Duve Institute, Université catholique de Louvain, Brussels, Belgium
› Author Affiliations
Funding This work was supported by the Fonds de la Recherche Scientifique (FNRS), grant Télévie 7.8505.21, the Fonds Joseph Maisin, grants 2020-2021 and 2022-2023, and the Foundation against Cancer, grant 2018-078. LTPA is Research fellow of the Fonds de la Recherche Scientifique (FNRS), fellowship 1.A.424.24F.


Biliary tract cancer is a devastating malignancy of the bile ducts and gallbladder with a dismal prognosis. The study of precancerous lesions has received considerable attention and led to a histopathological classification which, in some respects, remains an evolving field. Consequently, increasing efforts have been devoted to characterizing the molecular pathogenesis of the precursor lesions, with the aim of better understanding the mechanisms of tumor progression, and with the ultimate goal of meeting the challenges of early diagnosis and treatment. This review delves into the molecular mechanisms that initiate and promote the development of precursor lesions of intra- and extrahepatic cholangiocarcinoma and of gallbladder carcinoma. It addresses the genomic, epigenomic, and transcriptomic landscape of these precursors and provides an overview of animal and organoid models used to study them. In conclusion, this review summarizes the known molecular features of precancerous lesions in biliary tract cancer and highlights our fragmentary knowledge of the molecular pathogenesis of tumor initiation.

Publication History

Accepted Manuscript online:
09 November 2023

Article published online:
15 December 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Sung H, Ferlay J, Siegel RL. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (03) 209-249
  • 2 Koshiol J, Yu B, Kabadi SM, Baria K, Shroff RT. Epidemiologic patterns of biliary tract cancer in the United States: 2001-2015. BMC Cancer 2022; 22 (01) 1178
  • 3 Roa JC, Adsay NV, Arola J. et al. Carcinoma of the gallbladder. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 283-288
  • 4 Roa JC, García P, Kapoor VK, Maithel SK, Javle M, Koshiol J. Gallbladder cancer. Nat Rev Dis Primers 2022; 8 (01) 69
  • 5 Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol 2014; 6: 99-109
  • 6 Muraki T, Pehlivanoglu B, Memis B. et al. Pancreatobiliary maljunction-associated gallbladder cancer is as common in the West, shows distinct clinicopathologic characteristics and offers an invaluable model for anatomy-induced reflux-associated physio-chemical carcinogenesis. Ann Surg 2022; 276 (01) e32-e39
  • 7 Nakanuma Y, Klimstra DS, Komuta M. et al. Intrahepatic cholangiocarcinoma. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 254-259
  • 8 Banales JM, Marin JJG, Lamarca A. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol 2020; 17 (09) 557-588
  • 9 Kanno N, LeSage G, Glaser S, Alvaro D, Alpini G. Functional heterogeneity of the intrahepatic biliary epithelium. Hepatology 2000; 31 (03) 555-561
  • 10 Lemaigre FP. Development of the intrahepatic and extrahepatic biliary tract: a framework for understanding congenital diseases. Annu Rev Pathol 2020; 15: 1-22
  • 11 Pepe-Mooney BJ, Dill MT, Alemany A. et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 2019; 25 (01) 23-38.e8
  • 12 Tulasi DY, Castaneda DM, Wager K. et al. Sox9(EGFP) defines biliary epithelial heterogeneity downstream of Yap activity. Cell Mol Gastroenterol Hepatol 2021; 11 (05) 1437-1462
  • 13 Andrews TS, Atif J, Liu JC. et al. Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol Commun 2022; 6 (04) 821-840
  • 14 Sampaziotis F, Muraro D, Tysoe OC. et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 2021; 371 (6531): 839-846
  • 15 Brindley PJ, Bachini M, Ilyas SI. et al. Cholangiocarcinoma. Nat Rev Dis Primers 2021; 7 (01) 65
  • 16 Kuipers H, de Bitter TJJ, de Boer MT. et al. Gallbladder cancer: current insights in genetic alterations and their possible therapeutic implications. Cancers (Basel) 2021; 13 (21) 5257
  • 17 Nakanuma Y, Kakuda Y, Sugino T, Sato Y, Fukumura Y. Pathologies of precursor lesions of biliary tract carcinoma. Cancers (Basel) 2022; 14 (21) 5358
  • 18 Nakanuma Y, Uesaka K, Kakuda Y. et al. Intraductal papillary neoplasm of bile duct: updated clinicopathological characteristics and molecular and genetic alterations. J Clin Med 2020; 9 (12) 3991
  • 19 Fukumura Y, Rong L, Maimaitiaili Y. et al. Precursor lesions of gallbladder carcinoma: disease concept, pathology, and genetics. Diagnostics (Basel) 2022; 12 (02) 341
  • 20 Roa I, Araya JC, Villaseca M. et al. Preneoplastic lesions and gallbladder cancer: an estimate of the period required for progression. Gastroenterology 1996; 111 (01) 232-236
  • 21 Albores-Saavedra J, Alcántra-Vazquez A, Cruz-Ortiz H, Herrera-Goepfert R. The precursor lesions of invasive gallbladder carcinoma. Hyperplasia, atypical hyperplasia and carcinoma in situ. Cancer 1980; 45 (05) 919-927
  • 22 Yamagiwa H, Tomiyama H. Intestinal metaplasia-dysplasia-carcinoma sequence of the gallbladder. Acta Pathol Jpn 1986; 36 (07) 989-997
  • 23 Roa JC, Basturk O, Adsay V. Dysplasia and carcinoma of the gallbladder: pathological evaluation, sampling, differential diagnosis and clinical implications. Histopathology 2021; 79 (01) 2-19
  • 24 Seretis C, Lagoudianakis E, Gemenetzis G, Seretis F, Pappas A, Gourgiotis S. Metaplastic changes in chronic cholecystitis: implications for early diagnosis and surgical intervention to prevent the gallbladder metaplasia-dysplasia-carcinoma sequence. J Clin Med Res 2014; 6 (01) 26-29
  • 25 Bal MM, Ramadwar M, Deodhar K, Shrikhande S. Pathology of gallbladder carcinoma: current understanding and new perspectives. Pathol Oncol Res 2015; 21 (03) 509-525
  • 26 Mukhopadhyay S, Landas SK. Putative precursors of gallbladder dysplasia: a review of 400 routinely resected specimens. Arch Pathol Lab Med 2005; 129 (03) 386-390
  • 27 Basturk O, Aishima S, Esposito I. Biliary intraepithelial neoplasia. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 273-275
  • 28 Sarcognato S, Sacchi D, Fassan M. et al. Benign biliary neoplasms and biliary tumor precursors. Pathologica 2021; 113 (03) 147-157
  • 29 Kozuka S, Tsubone N, Yasui A, Hachisuka K. Relation of adenoma to carcinoma in the gallbladder. Cancer 1982; 50 (10) 2226-2234
  • 30 Basturk O, Aishima S, Esposito I. Pyloric gland adenoma of the gallbladder. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 271-272
  • 31 Basturk O, Aishima S, Esposito I. Intracholecystic papillary neoplasm. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 271-272
  • 32 Koike D, Kato H, Asano Y. et al. Natural history of intracholecystic papillary neoplasm (ICPN): a rare case of ICPN whose natural history was closely followed by ultrasound. BMC Gastroenterol 2022; 22 (01) 377
  • 33 Muraki T, Memis B, Reid MD. et al. Reflux-associated cholecystopathy: analysis of 76 gallbladders from patients with supra-Oddi union of the pancreatic duct and common bile duct (pancreatobiliary maljunction) elucidates a specific diagnostic pattern of mucosal hyperplasia as a prelude to carcinoma. Am J Surg Pathol 2017; 41 (09) 1167-1177
  • 34 Nakanuma Y, Basturk O, Esposito I. et al. Intraductal papillary neoplasms of the bile ducts. In: WHO Classification of Tumours Editorial Board, Digestive System Tumours. 5th ed.. World Health Organization; 2019: 279-282
  • 35 Onoe S, Ebata T, Yokoyama Y. et al. A clinicopathological reappraisal of intraductal papillary neoplasm of the bile duct (IPNB): a continuous spectrum with papillary cholangiocarcinoma in 181 curatively resected cases. HPB (Oxford) 2021; 23 (10) 1525-1532
  • 36 Wang T, Askan G, Ozcan K. et al. Tumoral intraductal neoplasms of the bile ducts comprise morphologically and genetically distinct entities. Arch Pathol Lab Med 2023; 147 (12) 1390-1401
  • 37 Pehlivanoglu B, Adsay V. Intraductal tubulopapillary neoplasms of the bile ducts: identity, clinicopathologic characteristics, and differential diagnosis of a distinct entity among intraductal tumors. Hum Pathol 2023; 132: 12-19
  • 38 Barreto SG, Dutt A, Chaudhary A. A genetic model for gallbladder carcinogenesis and its dissemination. Ann Oncol 2014; 25 (06) 1086-1097
  • 39 Moreno M, Pimentel F, Gazdar AF, Wistuba II, Miquel JF. TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma. Ann Hepatol 2005; 4 (03) 192-199
  • 40 Wistuba II, Gazdar AF, Roa I, Albores-Saavedra J. p53 protein overexpression in gallbladder carcinoma and its precursor lesions: an immunohistochemical study. Hum Pathol 1996; 27 (04) 360-365
  • 41 Lin J, Peng X, Dong K. et al. Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer. Nat Commun 2021; 12 (01) 4753
  • 42 Jiao Y, Pawlik TM, Anders RA. et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet 2013; 45 (12) 1470-1473
  • 43 Li M, Zhang Z, Li X. et al. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet 2014; 46 (08) 872-876
  • 44 Nakamura H, Arai Y, Totoki Y. et al. Genomic spectra of biliary tract cancer. Nat Genet 2015; 47 (09) 1003-1010
  • 45 Wardell CP, Fujita M, Yamada T. et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol 2018; 68 (05) 959-969
  • 46 Mehrotra R, Tulsyan S, Hussain S. et al. Genetic landscape of gallbladder cancer: Global overview. Mutat Res Rev Mutat Res 2018; 778: 61-71
  • 47 Montal R, Sia D, Montironi C. et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol 2020; 73 (02) 315-327
  • 48 Ebata N, Fujita M, Sasagawa S. et al. Molecular classification and tumor microenvironment characterization of gallbladder cancer by comprehensive genomic and transcriptomic analysis. Cancers (Basel) 2021; 13 (04) 733
  • 49 Nepal C, Zhu B, O'Rourke CJ. et al; CGR Exome Studies Group. Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes. J Hepatol 2021; 74 (05) 1132-1144
  • 50 Jain K, Mohapatra T, Das P. et al. Sequential occurrence of preneoplastic lesions and accumulation of loss of heterozygosity in patients with gallbladder stones suggest causal association with gallbladder cancer. Ann Surg 2014; 260 (06) 1073-1080
  • 51 Kang M, Na HY, Ahn S. et al. Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors. eLife 2022; 11: e78636
  • 52 Yanagisawa N, Mikami T, Saegusa M, Okayasu I. More frequent beta-catenin exon 3 mutations in gallbladder adenomas than in carcinomas indicate different lineages. Cancer Res 2001; 61 (01) 19-22
  • 53 Chang HJ, Jee CD, Kim WH. Mutation and altered expression of beta-catenin during gallbladder carcinogenesis. Am J Surg Pathol 2002; 26 (06) 758-766
  • 54 He C, Fukumura Y, Toriyama A. et al. Pyloric gland adenoma (PGA) of the gallbladder: a unique and distinct tumor from PGAs of the stomach, duodenum, and pancreas. Am J Surg Pathol 2018; 42 (09) 1237-1245
  • 55 Akita M, Fujikura K, Ajiki T. et al. Intracholecystic papillary neoplasms are distinct from papillary gallbladder cancers: a clinicopathologic and exome-sequencing study. Am J Surg Pathol 2019; 43 (06) 783-791
  • 56 Iwasaki T, Otsuka Y, Miyata Y. et al. Intracholecystic papillary neoplasm arising in a patient with pancreaticobiliary maljunction: a case report. World J Surg Oncol 2020; 18 (01) 292
  • 57 Pai RK, Mojtahed K, Pai RK. Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. Appl Immunohistochem Mol Morphol 2011; 19 (02) 133-140
  • 58 Kawakami S, Takano S, Fukasawa M. et al. Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study. BMC Cancer 2021; 21 (01) 1245
  • 59 House MG, Wistuba II, Argani P. et al. Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. Ann Surg Oncol 2003; 10 (08) 882-889
  • 60 Takahashi T, Shivapurkar N, Riquelme E. et al. Aberrant promoter hypermethylation of multiple genes in gallbladder carcinoma and chronic cholecystitis. Clin Cancer Res 2004; 10 (18 Pt 1): 6126-6133
  • 61 García P, Manterola C, Araya JC. et al. Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Mol Carcinog 2009; 48 (01) 79-89
  • 62 Sharma P, Bhunia S, Poojary SS. et al. Global methylation profiling to identify epigenetic signature of gallbladder cancer and gallstone disease. Tumour Biol 2016; 37 (11) 14687-14699
  • 63 Letelier P, Brebi P, Tapia O, Roa JC. DNA promoter methylation as a diagnostic and therapeutic biomarker in gallbladder cancer. Clin Epigenetics 2012; 4 (01) 11
  • 64 Brägelmann J, Barahona Ponce C, Marcelain K. et al. Epigenome-wide analysis of methylation changes in the sequence of gallstone disease, dysplasia, and gallbladder cancer. Hepatology 2021; 73 (06) 2293-2310
  • 65 Feng Z, Chen J, Wei H. et al. The risk factor of gallbladder cancer: hyperplasia of mucous epithelium caused by gallstones associates with p16/CyclinD1/CDK4 pathway. Exp Mol Pathol 2011; 91 (02) 569-577
  • 66 Hsu M, Sasaki M, Igarashi S, Sato Y, Nakanuma Y. KRAS and GNAS mutations and p53 overexpression in biliary intraepithelial neoplasia and intrahepatic cholangiocarcinomas. Cancer 2013; 119 (09) 1669-1674
  • 67 Sasaki M, Nitta T, Sato Y, Nakanuma Y. Autophagy may occur at an early stage of cholangiocarcinogenesis via biliary intraepithelial neoplasia. Hum Pathol 2015; 46 (02) 202-209
  • 68 Nakanishi Y, Zen Y, Kondo S, Itoh T, Itatsu K, Nakanuma Y. Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol 2008; 39 (08) 1153-1161
  • 69 Loeffler MA, Hu J, Kirchner M. et al. miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis. J Pathol 2020; 252 (03) 239-251
  • 70 Itatsu K, Zen Y, Ohira S. et al. Immunohistochemical analysis of the progression of flat and papillary preneoplastic lesions in intrahepatic cholangiocarcinogenesis in hepatolithiasis. Liver Int 2007; 27 (09) 1174-1184
  • 71 Yang CY, Huang WJ, Tsai JH. et al. Targeted next-generation sequencing identifies distinct clinicopathologic and molecular entities of intraductal papillary neoplasms of the bile duct. Mod Pathol 2019; 32 (11) 1637-1645
  • 72 Aoki Y, Mizuma M, Hata T. et al. Intraductal papillary neoplasms of the bile duct consist of two distinct types specifically associated with clinicopathological features and molecular phenotypes. J Pathol 2020; 251 (01) 38-48
  • 73 Goeppert B, Stichel D, Toth R. et al. Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis. Gut 2022; 71 (02) 391-401
  • 74 Ong CK, Subimerb C, Pairojkul C. et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet 2012; 44 (06) 690-693
  • 75 Sasaki M, Matsubara T, Nitta T, Sato Y, Nakanuma Y. GNAS and KRAS mutations are common in intraductal papillary neoplasms of the bile duct. PLoS One 2013; 8 (12) e81706
  • 76 Matthaei H, Wu J, Dal Molin M. et al. GNAS codon 201 mutations are uncommon in intraductal papillary neoplasms of the bile duct. HPB (Oxford) 2012; 14 (10) 677-683
  • 77 Tsai JH, Liau JY, Yuan CT, Cheng ML, Yuan RH, Jeng YM. RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct. Histopathology 2017; 70 (05) 756-765
  • 78 Tsai JH, Yuan RH, Chen YL, Liau JY, Jeng YM. GNAS Is frequently mutated in a specific subgroup of intraductal papillary neoplasms of the bile duct. Am J Surg Pathol 2013; 37 (12) 1862-1870
  • 79 Nakanuma Y, Kakuda Y, Fukumura Y. et al. The pathologic and genetic characteristics of the intestinal subtype of intraductal papillary neoplasms of the bile duct. Am J Surg Pathol 2019; 43 (09) 1212-1220
  • 80 Fujikura K, Akita M, Ajiki T, Fukumoto T, Itoh T, Zen Y. Recurrent mutations in APC and CTNNB1 and activated Wnt/beta-catenin signaling in intraductal papillary neoplasms of the bile duct: a whole exome sequencing study. Am J Surg Pathol 2018; 42 (12) 1674-1685
  • 81 Singhi AD, Wood LD, Parks E. et al. Recurrent rearrangements in PRKACA and PRKACB in intraductal oncocytic papillary neoplasms of the pancreas and bile duct. Gastroenterology 2020; 158 (03) 573-582.e2
  • 82 Schlitter AM, Born D, Bettstetter M. et al. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Mod Pathol 2014; 27 (01) 73-86
  • 83 Sasaki M, Matsubara T, Yoneda N. et al. Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct. Histopathology 2013; 62 (03) 446-457
  • 84 Gross C, Engleitner T, Lange S. et al. Whole exome sequencing of biliary tubulopapillary neoplasms reveals common mutations in chromatin remodeling genes. Cancers (Basel) 2021; 13 (11) 2742
  • 85 Abraham SC, Lee JH, Hruban RH, Argani P, Furth EE, Wu TT. Molecular and immunohistochemical analysis of intraductal papillary neoplasms of the biliary tract. Hum Pathol 2003; 34 (09) 902-910
  • 86 Gérard C, Di-Luoffo M, Gonay L. et al. Dynamics and predicted drug response of a gene network linking dedifferentiation with beta-catenin dysfunction in hepatocellular carcinoma. J Hepatol 2019; 71 (02) 323-332
  • 87 Doi R, Fukumura Y, Lu R. et al. DNMT1 expression and DNA methylation in intraductal papillary neoplasms of the bile duct. Anticancer Res 2022; 42 (06) 2893-2902
  • 88 Loeuillard E, Fischbach SR, Gores GJ, Rizvi S. Animal models of cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis 2019; 1865 (05) 982-992
  • 89 Cadamuro M, Brivio S, Stecca T. et al. Animal models of cholangiocarcinoma: what they teach us about the human disease. Clin Res Hepatol Gastroenterol 2018; 42 (05) 403-415
  • 90 Pirenne S, Lemaigre FP. Genetically engineered animal models of biliary tract cancers. Curr Opin Gastroenterol 2020; 36 (02) 90-98
  • 91 Calvisi DF, Boulter L, Vaquero J. et al; CCA Model Consortium. Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance. Nat Rev Gastroenterol Hepatol 2023; 20 (07) 462-480
  • 92 Nakagawa H, Suzuki N, Hirata Y. et al. Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. Proc Natl Acad Sci U S A 2017; 114 (19) E3806-E3815
  • 93 Lesaffer B, Verboven E, Van Huffel L. et al. Comparison of the Opn-CreER and Ck19-CreER drivers in bile ducts of normal and injured mouse livers. Cells 2019; 8 (04) 380
  • 94 Nagao M, Fukuda A, Omatsu M. et al. Concurrent activation of KRAS and canonical Wnt signaling induces premalignant lesions that progress to extrahepatic biliary cancer in mice. Cancer Res 2022; 82 (09) 1803-1817
  • 95 Xu X, Kobayashi S, Qiao W. et al. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 2006; 116 (07) 1843-1852
  • 96 O'Dell MR, Huang JL, Whitney-Miller CL. et al. KRAS (G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma. Cancer Res 2012; 72 (06) 1557-1567
  • 97 Ikenoue T, Terakado Y, Nakagawa H. et al. A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific KRAS activation and Pten deletion. Sci Rep 2016; 6: 23899
  • 98 Hill MA, Alexander WB, Guo B. et al. KRAS and Tp53 mutations cause cholangiocyte- and hepatocyte-derived cholangiocarcinoma. Cancer Res 2018; 78 (16) 4445-4451
  • 99 Lin YK, Fang Z, Jiang TY. et al. Combination of KRAS activation and PTEN deletion contributes to murine hepatopancreatic ductal malignancy. Cancer Lett 2018; 421: 161-169
  • 100 Di-Luoffo M, Pirenne S, Saandi T. et al. A novel mouse model of cholangiocarcinoma uncovers a role for Tensin-4 in tumor progression. Hepatology 2021; 74 (03) 1445-1460
  • 101 Namikawa M, Fukuda A, Mizukoshi K. et al. Simultaneous activation of KRAS-Akt and Notch pathways induces extrahepatic biliary cancer via the mTORC1 pathway. J Pathol 2023; 260 (04) 478-492
  • 102 Tomita H, Tanaka K, Hirata A. et al. Inhibition of FGF10-ERK signal activation suppresses intraductal papillary neoplasm of the bile duct and its associated carcinomas. Cell Rep 2021; 34 (08) 108772
  • 103 Marsh V, Davies EJ, Williams GT, Clarke AR. PTEN loss and KRAS activation cooperate in murine biliary tract malignancies. J Pathol 2013; 230 (02) 165-173
  • 104 Chung WC, Wang J, Zhou Y, Xu K. KRASG12D upregulates Notch signaling to induce gallbladder tumorigenesis in mice. Oncoscience 2017; 4 (9–10): 131-138
  • 105 Gabbi C, Kim HJ, Barros R, Korach-Andrè M, Warner M, Gustafsson JA. Estrogen-dependent gallbladder carcinogenesis in LXRbeta-/- female mice. Proc Natl Acad Sci U S A 2010; 107 (33) 14763-14768
  • 106 Rosa L, Lobos-González L, Muñoz-Durango N. et al. Evaluation of the chemopreventive potentials of ezetimibe and aspirin in a novel mouse model of gallbladder preneoplasia. Mol Oncol 2020; 14 (11) 2834-2852
  • 107 Yeh CN, Maitra A, Lee KF, Jan YY, Chen MF. Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. Carcinogenesis 2004; 25 (04) 631-636
  • 108 Marsee A, Roos F, Verstegen M. et al. Building a consensus on definition and nomenclature of human hepatic, biliary and pancreatic organoids. Cell Stem Cell 2021; 28: 816-832
  • 109 Yuan B, Zhao X, Wang X. et al. Patient-derived organoids for personalized gallbladder cancer modelling and drug screening. Clin Transl Med 2022; 12 (01) e678
  • 110 Broutier L, Mastrogiovanni G, Verstegen MM. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 2017; 23 (12) 1424-1435
  • 111 Saito Y, Muramatsu T, Kanai Y. et al. Establishment of patient-derived organoids and drug screening for biliary tract carcinoma. Cell Rep 2019; 27 (04) 1265-1276.e4
  • 112 Maier CF, Zhu L, Nanduri LK. et al. Patient-derived organoids of cholangiocarcinoma. Int J Mol Sci 2021; 22 (16) 8675
  • 113 Fujii M, Shimokawa M, Date S. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 2016; 18 (06) 827-838
  • 114 Huch M, Gehart H, van Boxtel R. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2015; 160 (1–2): 299-312