Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation
Open accessAbstract
OBJECTIVES: Emerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia. DESIGN: To investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCre(late); Nr5a2(c/c)). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion. RESULTS: We show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions. CONCLUSIONS: Nr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.
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Heterozygous or homozygous deletion of terminal acinar differentiation factors Ptf1a, Mist1, and Nr5a2 accelerates KRAS-driven tumorigenesis.
“heterozygous or homozygous deletion of factors associated with terminal acinar differentiation such as Ptf1a, Mist1, and Nr5a2 accelerate KRAS-driven tumorigenesis119–122.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [119]
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Cites
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus
Srinivas, S., Watanabe, T., Lin, C.-S., William, C. M., Tanabe, Y., Jessell, T. M., & Costantini, F. (2001) · BMC Developmental Biology · doi:10.1186/1471-213x-1-4 · Cited by 3,121 · see citing works
Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., et al. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00309-x · Cited by 2,471 · see citing works
Self-citationPancreatitis and the Risk of Pancreatic Cancer
Lowenfels, A. B., Maisonneuve, P., Cavallini, G., Ammann, R., Lankisch, P. G., Andersen, J. R., DiMagno, E. P., Andrén‐Sandberg, Å., & Domellöf, L. (1993) · New England Journal of Medicine · doi:10.1056/nejm199305203282001 · Cited by 1,753 · see citing works
Guerra, C., Schuhmacher, A. J., Cañamero, M., Grippo, P. J., Verdaguer, L., Pérez-Gallego, L., Dubus, P., Sandgren, E. P., & Barbacid, M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.01.012 · Cited by 1,224 · see citing works
The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors
Kawaguchi, Y., Cooper, B., Gannon, M., Ray, M., MacDonald, R. J., & Wright, C. V. E. (2002) · Nature Genetics · doi:10.1038/ng959 · Cited by 1,007 · see citing works
Self-citationOncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice
Collins, M. A., Bednar, F., Zhang, Y., Brisset, J.-C., Galbán, S., Galbán, C. J., Rakshit, S., Flannagan, K. S., Adsay, N. V., & Pasca di Magliano, M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59227 · Cited by 770 · see citing works
Kopp, J. L., von Figura, G., Mayes, E., Liu, F.-F., Dubois, C. L., Morris, J. P., Pan, F. C., Akiyama, H., Wright, C. V. E., Jensen, K., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.025 · Cited by 697 · see citing works
Self-citationPetersen, G. M., Amundadottir, L. T., Fuchs, C. S., Kraft, P., Stolzenberg‐Solomon, R. Z., Jacobs, K. B., Arslan, A. A., Bueno-de-Mesquita, H. B., Gallinger, S., Gross, M. D., et al. (2010) · Nature Genetics · doi:10.1038/ng.522 · Cited by 596 · see citing works
KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma
Morris, J. P., Wang, S. C., & Hebrok, M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2899 · Cited by 567 · see citing works
Self-citationStat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and Progression
Fukuda, A., Wang, S. C., Morris, J. P., Folias, A. E., Liou, A., Kim, G. E., Akira, S., Boucher, K., Firpo, M., Mulvihill, S., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.03.002 · Cited by 531 · see citing works
Self-citationHabbe, N., Shi, G., Meguid, R. A., Fendrich, V., Esni, F., Chen, H., Feldmann, G., Stoffers, D. A., Konieczny, S. F., Leach, S. D., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810097105 · Cited by 410 · see citing works
Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia
Jean–Paul De La, O., Emerson, L. L., Goodman, J. L., Froebe, S. C., Illum, B. E., Curtis, A. B., & Murtaugh, L. C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810111105 · Cited by 396 · see citing works
Morris, J. P., Cano, D., Sekine, S., Wang, S. C., & Hebrok, M. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40045 · Cited by 391 · see citing works
Self-citationRecapitulation of elements of embryonic development in adult mouse pancreatic regeneration.
Jensen, J., Cameron, E., Garay, M., Starkey, T. W., Gianani, R., & Jensen, J. (2005) · Gastroenterology · doi:10.1053/j.gastro.2004.12.008 · Cited by 361 · see citing works
Means, A. L., Meszoely, I. M., Suzuki, K., Miyamoto, Y., Rustgi, A. K., Coffey, R. J., Wright, C. V. E., Stoffers, D. A., & Leach, S. D. (2005) · Development · doi:10.1242/dev.01925 · Cited by 344 · see citing works
Self-citationContext-Dependent Transformation of Adult Pancreatic Cells by Oncogenic K-Ras
Friedlander, S., Chu, G. C., Snyder, E. L., Girnius, N., Dibelius, G., Crowley, D. G., Vasile, E., DePinho, R. A., & Jacks, T. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.09.027 · Cited by 338 · see citing works
Pan, F. C., Bankaitis, E., Boyer, D. F., Xu, X.-B., de Casteele, M. V., Magnuson, M., Heimberg, H., & Wright, C. (2013) · Development · doi:10.1242/dev.090159 · Cited by 299 · see citing works
Self-citationDaniluk, J., Liu, Y., Deng, D., Chu, J., Huang, H., Gaiser, S., Cruz‐Monserrate, Z., Wang, H., Ji, B., & Logsdon, C. D. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59743 · Cited by 277 · see citing works
Pin, C. L., Rukstalis, J. M., Johnson, C., & Konieczny, S. F. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200105060 · Cited by 276 · see citing works
Carrière, C., Young, A. L., Gunn, J. R., Longnecker, D. S., & Korc, M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.03.068 · Cited by 236 · see citing works
Acinar Cells Contribute to the Molecular Heterogeneity of Pancreatic Intraepithelial Neoplasia
Zhu, L., Shi, G., Schmidt, C. M., Hruban, R. H., & Konieczny, S. F. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.061176 · Cited by 213 · see citing works
Hedgehog Signaling Is Required for Effective Regeneration of Exocrine Pancreas
Fendrich, V., Esni, F., Garay, M. V. R., Feldmann, G., Habbe, N., Jensen, J. N., Dor, Y., Stoffers, D., Jensen, J., Leach, S. D., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.04.011 · Cited by 191 · see citing works
Shi, G., Zhu, L., Sun, Y., Bettencourt, R., Damsz, B., Hruban, R. H., & Konieczny, S. F. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.12.066 · Cited by 168 · see citing works
Shi, G., DiRenzo, D., Qu, C., Barney, D., Miley, D., & Konieczny, S. F. (2013) · Oncogene · doi:10.1038/onc.2012.210 · Cited by 162 · see citing works
Stabilization of β-catenin induces pancreas tumor formation
Heiser, P., Cano, D., Landsman, L., Kim, G. E., Kench, J., Klimstra, D., Taketo, M., Biankin, A., & Hebrok, M. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.089 · Cited by 155 · see citing works
Self-citationLee, Y.-K., Schmidt, D. R., Cummins, C. L., Choi, M., Peng, L., Zhang, Y., Goodwin, B. J., Hammer, R. E., Mangelsdorf, D. J., & Kliewer, S. A. (2008) · Molecular Endocrinology · doi:10.1210/me.2007-0565 · Cited by 151 · see citing works
Houbracken, I., Waele, E. D., Lardon, J., Ling, Z., Heimberg, H., Rooman, I., & Bouwens, L. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.04.050 · Cited by 143 · see citing works
Pinho, A. V., Rooman, I., Reichert, M., De Medts, N., Bouwens, L., Rustgi, A. K., & Real, F. X. (2011) · Gut · doi:10.1136/gut.2010.225920 · Cited by 129 · see citing works
Benod, C. C., Vinogradova, M. V., Jouravel, N., Kim, G., Fletterick, R. J., & Sablin, E. P. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112047108 · Cited by 128 · see citing works
Masui, T., Swift, G. H., Deering, T. G., Shen, C.-C., Coats, W. S., Long, Q.-M., Elsässer, H., Magnuson, M., & MacDonald, R. J. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.04.003 · Cited by 118 · see citing works
The Role of PTF1-P48 in Pancreatic Acinar Gene Expression
Rose, S. D., Swift, G. H., Peyton, M. J., Hammer, R. E., & MacDonald, R. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m106264200 · Cited by 111 · see citing works
Shi, C., Hong, S., Lim, P., Kamiyama, H., Khan, M. A., Anders, R. A., Goggins, M., Hruban, R. H., & Eshleman, J. R. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0206 · Cited by 109 · see citing works
Holmstrom, S. R., Deering, T. G., Swift, G. H., Poelwijk, F. J., Mangelsdorf, D. J., Kliewer, S. A., & MacDonald, R. J. (2011) · Genes & Development · doi:10.1101/gad.16860911 · Cited by 107 · see citing works
Li, D., Duell, E. J., Yu, K. F., Risch, H. A., Olson, S. H., Kooperberg, C. L., Wolpin, B. M., Jiao, L., Dong, X., Wheeler, B., et al. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs151 · Cited by 106 · see citing works
Martinelli, P., Cañamero, M., Pozo, N. D., Madriles, F., Zapata, A., & Real, F. (2012) · Gut · doi:10.1136/gutjnl-2012-303328 · Cited by 102 · see citing works
Schreiber, F. S., Deramaudt, T. B., Brunner, T. B., Boretti, M. I., Gooch, K. J., Stoffers, D. A., Bernhard, E. J., & Rustgi, A. K. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.03.058 · Cited by 102 · see citing works
Flandez, M., Cendrowski, J., Cañamero, M., Salas, A., del Pozo, N., Schoonjans, K., & Real, F. X. (2014) · Gut · doi:10.1136/gutjnl-2012-304381 · Cited by 95 · see citing works
Demographics and Epidemiology of Pancreatic Cancer
Yeo, T. P., & Lowenfels, A. B. (2012) · The Cancer Journal · doi:10.1097/ppo.0b013e3182756803 · Cited by 78 · see citing works
Nagashio, Y., Ueno, H., Imamura, M., et al. (2004) · Laboratory Investigation · doi:10.1038/labinvest.3700191 · Cited by 71 · see citing works
Pancreatic Cancer Susceptibility Loci and Their Role in Survival
Rizzato, C., Campa, D., Giese, N. A., Werner, J., Rachakonda, P. S., Kumar, R., Schanné, M., Greenhalf, W., Costello, E., Khaw, K., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027921 · Cited by 56 · see citing works
Molero, X., Vaquero, E., Flández, M., González, A., Ortiz, M. A., Cibrián-Uhalte, E., Servitja, J., Merlos, A. M., Juanpere, N., Massumi, M., et al. (2011) · Gut · doi:10.1136/gutjnl-2011-300360 · Cited by 49 · see citing works
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Self-citation
- Authors
- von Figura, G., Morris, J. P., Wright, C. V. E., & Hebrok, M.
- Affiliations
- University of California, San Francisco (US)
- Vanderbilt University (US)
- Corresponding author
- Hebrok, Matthias
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2013-05-03
- Volume
- 63
- Issue
- 4
- Pages
- 656-664
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC3883808
- OpenAlex
- W2169837598
- Cited by
- 143
- References
- 41
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 11 · 2023: 14 · 2022: 2 · 2021: 19 · 2020: 9 · 2019: 13 · 2018: 17 · 2017: 7 · 2016: 12 · 2015: 18 · 2014: 8 · 2013: 7
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- University of California, San Francisco
- National Cancer Institute (R01CA112537)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-63720, U19DK042502, U01DK089570, P30DK063720)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- NR5A2, acinar differentiation, acinar-to-ductal metaplasia, pancreatic ductal adenocarcinoma, oncogenic KRAS, pancreatic neoplasia, pancreatic regeneration, pancreatic precancerous lesions
- MeSH terms
- Animals, Ceruletide, Cell Differentiation, Cell Line, Cell Transformation, Neoplastic, Pancreatic Neoplasms, Pancreatitis, Proto-Oncogene Proteins p21(ras), Receptors, Cytoplasmic and Nuclear, Carcinoma, Acinar Cell, Carcinoma, Pancreatic Ductal, Mice, Real-Time Polymerase Chain Reaction
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