Cell of origin affects tumour development and phenotype in pancreatic ductal adenocarcinoma
Open accessAbstract
Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumour thought to arise from ductal cells via pancreatic intraepithelial neoplasia (PanIN) precursor lesions. Modelling of different genetic events in mice suggests both ductal and acinar cells can give rise to PDAC. However, the impact of cellular context alone on tumour development and phenotype is unknown. Design: We examined the contribution of cellular origin to PDAC development by inducing PDAC-associated mutations, Kras G12D expression and Trp53 loss, specifically in ductal cells ( Sox9CreER;Kras LSL-G12D ;Trp53 flox/flox (‘ Duct:KP cKO ’)) or acinar cells ( Ptf1a CreER ;Kras LSL-G12D ;Trp53 flox/flox (‘ Acinar:KP cKO ’)) in mice. We then performed a thorough analysis of the resulting histopathological changes. Results: Both mouse models developed PDAC, but Duct:KP cKO mice developed PDAC earlier than Acinar:KP cKO mice. Tumour development was more rapid and associated with high-grade murine PanIN (mPanIN) lesions in Duct:KP cKO mice. In contrast, Acinar:KP cKO mice exhibited widespread metaplasia and low-grade as well as high-grade mPanINs with delayed progression to PDAC. Acinar-cell-derived tumours also had a higher prevalence of mucinous glandular features reminiscent of early mPanIN lesions. Conclusion: These findings indicate that ductal cells are primed to form carcinoma in situ that become invasive PDAC in the presence of oncogenic Kras and Trp53 deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Deletion of Trp53 in the adult ductal lineage leads to rapid development of invasive carcinoma in mice.
“the deletion of Trp53 leads to the rapid development of invasive carcinoma125–127.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Genomic analyses identify molecular subtypes of pancreatic cancer
Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A.-M., Gingras, M.-C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., et al. (2016) · Nature · doi:10.1038/nature16965 · Cited by 3,621 · see citing works
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
Hingorani, S. R., Wang, L., Multani, A. S., Combs, C., Deramaudt, T. B., Hruban, R. H., Rustgi, A. K., Chang, S., & Tuveson, D. A. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.023 · Cited by 2,609 · see citing works
Moffitt, R. A., Marayati, R., Flate, E. L., Volmar, K. E., Loeza, S. G. H., Hoadley, K. A., Rashid, N. U., Williams, L. A., Eaton, S. C., Chung, A. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3398 · Cited by 2,194 · 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
Aguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · see citing works
Marino, S., Vooijs, M., van der Gulden, H., Jonkers, J., & Berns, A. (2000) · Genes & Development · doi:10.1101/gad.14.8.994 · Cited by 920 · see citing works
Progression model for pancreatic cancer.
Hruban, R. H., Goggins, M., Parsons, J., & Kern, S. E. (2000) · PubMed · Cited by 872 · see citing works
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798 · see citing works
Oncogenic 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
Sandgren, E. P., Luetteke, N., Palmiter, R. D., Brinster, R. L., & Lee, D. C. (1990) · Cell · doi:10.1016/0092-8674(90)90075-p · Cited by 752 · 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-citationHruban, R. H., van Mansfeld, A. D. M., Offerhaus, G. J. A., van Weering, D. H. J., Allison, D. C., Goodman, S. N., Kensler, T. W., Bose, K., Cameron, J. L., & Bos, J. L. (1993) · PubMed Central · Cited by 650 · see citing works
Bardeesy, N. M., Aguirre, A. J., Chu, G. C., Cheng, K., Lopez, L. V., Hezel, A. F., Feng, B., Brennan, C. W., Weissleder, R., Mahmood, U., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601273103 · Cited by 575 · see citing works
Guerra, C., Collado, M., Navas, C., Schuhmacher, A. J., Hernández-Porras, I., Cañamero, M., Rodriguez-Justo, M., Serrano, M., & Barbacid, M. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.05.011 · Cited by 516 · see citing works
Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer
Font-Burgada, J., Shalapour, S., Ramaswamy, S., Hsueh, B., Rossell, D., Umemura, A., Taniguchi, K., Nakagawa, H., Valasek, M. A., Ye, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.026 · Cited by 486 · see citing works
Self-citationKopp, J. L., Dubois, C. L., Schaffer, A., Hao, E., Shih, H., Seymour, P. A., Ma, J., & Sander, M. (2011) · Development · doi:10.1242/dev.056499 · Cited by 472 · 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
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
Pancreatic adenocarcinomas frequently show p53 gene mutations.
Scarpa, A., Capelli, P., Mukai, K., Zamboni, G., Oda, T., Iacono, C., & Hirohashi, S. (1993) · PubMed Central · Cited by 332 · 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
Strobel, O., Dor, Y., Alsina, J., Stirman, A., Lauwers, G. Y., Trainor, A. G., del Castillo, C. F., Warshaw, A. L., & Thayer, S. P. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.09.009 · Cited by 268 · see citing works
Kim, G., Bae, H., Park, H., Kuan, S., Crawley, S., Ho, J. J. L., & Kim, Y. S. (2002) · Gastroenterology · doi:10.1053/gast.2002.36018 · Cited by 252 · see citing works
Overexpression of p53 Protein in Adenocarcinoma of the Pancreas
DiGiuseppe, J. A., Hruban, R. H., Goodman, S. N., Polak, M., van den Berg, F. M., Allison, D. C., Cameron, J. L., & Offerhaus, G. J. A. (1994) · American Journal of Clinical Pathology · doi:10.1093/ajcp/101.6.684 · Cited by 217 · see citing works
Ras Activity Levels Control the Development of Pancreatic Diseases
Ji, B., Tsou, L., Wang, H., Gaiser, S., Chang, D. Z., Daniluk, J., Bi, Y., Grote, T., Longnecker, D. S., & Logsdon, C. D. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.05.052 · Cited by 194 · see citing works
von Figura, G., Fukuda, A., Roy, N., Liku, M. E., Morris IV, J. P., Kim, G. E., Russ, H. A., Firpo, M. A., Mulvihill, S. J., Dawson, D. W., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb2916 · Cited by 190 · see citing works
What We Have Learned About Pancreatic Cancer From Mouse Models
Pérez-Mancera, P. A., Guerra, C. E., Barbacid, M., & Tuveson, D. A. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.03.002 · Cited by 173 · 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
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma
Krah, N. M., De La O, J.-P., Swift, G. H., Hoang, C. Q., Willet, S. G., Chen Pan, F., Cash, G. M., Bronner, M. P., Wright, C. V., MacDonald, R. J., et al. (2015) · eLife · doi:10.7554/elife.07125 · Cited by 166 · 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
Genetic Progression and Divergence in Pancreatic Carcinoma
Yamano, M., Fujii, H., Takagaki, T., Kadowaki, N., Watanabe, H., & Shirai, T. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65083-3 · Cited by 160 · see citing works
Roy, N., Malik, S., Villanueva, K. E., Urano, A., Lu, X., Von Figura, G., Seeley, E. S., Dawson, D. W., Collisson, E. A., & Hebrok, M. (2015) · Genes & Development · doi:10.1101/gad.256628.114 · Cited by 155 · see citing works
p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells
Bailey, J. M., Hendley, A. M., Lafaro, K. J., Pruski, M. A., Jones, N. C., Alsina, J., Younes, M., Maitra, A., McAllister, F., Iacobuzio-Donahue, C. A., et al. (2016) · Oncogene · doi:10.1038/onc.2015.441 · Cited by 154 · see citing works
von Figura, G., Morris, J. P., Wright, C. V. E., & Hebrok, M. (2014) · Gut · doi:10.1136/gutjnl-2012-304287 · Cited by 143 · see citing works
A Dosage-Dependent Requirement for Sox9 in Pancreatic Endocrine Cell Formation
Seymour, P. A., Freude, K., Dubois, C. L., Shih, H., Patel, N., & Sander, M. (2008) · Developmental Biology · doi:10.1016/j.ydbio.2008.07.034 · Cited by 141 · see citing works
Self-citationFerreira, R. M. M., Sancho, R., Messal, H. A., Nye, E. L., Spencer‐Dene, B., Stone, R. K., Stamp, G., Rosewell, I. R., Quaglia, A., & Behrens, A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.093 · Cited by 130 · see citing works
Ray, K. C., Bell, K. M., Yan, J., Gu, G., Chung, C. H., Washington, M. K., & Means, A. L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016786 · Cited by 109 · see citing works
Ductal metaplasia of human exocrine pancreas and its association with carcinoma.
Parsa, I., Longnecker, D. S., Scarpelli, D. G., Pour, P. M., Reddy, J. K., & Lefkowitz, M. (1985) · PubMed · Cited by 103 · 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
Kopp, J. L., Dubois, C. L., Schaeffer, D. F., Samani, A., Taghizadeh, F., Cowan, R. W., Rhim, A. D., Stiles, B. L., Valasek, M., & Sander, M. (2018) · Gastroenterology · doi:10.1053/j.gastro.2017.12.007 · Cited by 80 · see citing works
Self-citationHassid, B. G., Lucas, A. L., Salomao, M. A., Weng, C., Liu, F., Khanna, L. G., Kumar, S., Hwang, C., Chabot, J. A., & Frucht, H. (2014) · Pancreas · doi:10.1097/mpa.0000000000000161 · Cited by 25 · see citing works
Oda, Y., Aishima, S., Morimatsu, K., et al. (2014) · Histopathology · doi:10.1111/his.12397 · Cited by 14 · see citing works
Miyazaki, T., Ohishi, Y., Miyasaka, Y., Oda, Y., Aishima, S., Ozono, K., Abe, A., Nagai, E., Nakamura, M., & Oda, Y. (2017) · Pathobiology · doi:10.1159/000455194 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
The pancreatic cancer genome revisited
Hayashi, A., Hong, J., & Iacobuzio-Donahue, C. A. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00463-z · Cited by 211 · see citing works
Cell of origin influences pancreatic cancer subtype
Flowers, B. M., Xu, H., Mulligan, A. S., Hanson, K. J., Seoane, J. A., Vogel, H., Curtis, C., Wood, L. D., & Attardi, L. D. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0633 · Cited by 118 · see citing works
SWI/SNF component <i>ARID1A</i> restrains pancreatic neoplasia formation
Wang, S. C., Nassour, I., Xiao, S., Zhang, S., Luo, X., Lee, J., Li, L., Sun, X., Nguyen, L. H., Chuang, J.-C., et al. (2019) · Gut · doi:10.1136/gutjnl-2017-315490 · Cited by 85 · see citing works
Genetic Mutations of Pancreatic Cancer and Genetically Engineered Mouse Models
Saiki, Y., Jiang, C., Ohmuraya, M., & Furukawa, T. (2021) · Cancers · doi:10.3390/cancers14010071 · Cited by 38 · see citing works
Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis
Shi, C., Pan, F. C., Kim, J. N., Washington, M. K., Padmanabhan, C., Meyer, C. T., Kopp, J. L., Sander, M., Gannon, M., Beauchamp, R. D., et al. (2019) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2019.07.001 · Cited by 21 · see citing works
Self-citation
- Authors
- Lee, A. Y. L., Dubois, C. L., Sarai, K., Zarei, S., Schaeffer, D. F., Sander, M., & Kopp, J. L.
- Affiliations
- University of British Columbia (CA)
- University of California San Diego (US)
- Corresponding author
- Kopp, Janel L
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2018-01-23
- Volume
- 68
- Issue
- 3
- Pages
- 487-498
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC11529381
- OpenAlex
- W2784916289
- Cited by
- 139
- References
- 45
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 13 · 2023: 23 · 2022: 14 · 2021: 35 · 2020: 15 · 2019: 12 · 2018: 8
- FWCI
- 6.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Pancreatic Cancer Canada Foundation
- Canadian Foundation for Innovation
- Pancreas Centre BC
- National Cancer Institute
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- pancreatic ductal adenocarcinoma, cell of origin, acinar cells, ductal cells, pancreatic intraepithelial neoplasia, KRAS G12D, Trp53 deletion, carcinogenesis, tumor progression, metaplasia, SOX9, Ptf1a, conditional knockout mice
- MeSH terms
- Animals, Carcinoma in Situ, Cell Transformation, Neoplastic, Disease Models, Animal, Mice, Inbred C57BL, Mutation, Pancreatic Neoplasms, Phenotype, Precancerous Conditions, Time Factors, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Mice, Knockout, Carcinoma, Pancreatic Ductal, Neoplasm Grading, Acinar Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
