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Precancerous neoplastic cells can move through the pancreatic ductal system
Open accessAbstract
Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.
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“Recent phylogenetic analyses of precursor lesions from the pancreata of patients with established cancer have confirmed the stepwise progression model and accumulation of genetic alterations in the transition from PanINs to PDAC postulated using more rudimentary techniques26.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [26]
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“Experimental evidence confirms the possibility of intraductal spread, as DNA sequencing has shown that adjacent, spatially separate PanIN sometimes harbor a similar profile of somatic mutations ( 14 , 19 ).”
BackgroundSelf-citationBraxton, A. M., Kiemen, A. L., Grahn, M. P., Forjaz, A., Babu, J. M., Zheng, L., Jiang, L., Cheng, H., Song, Q., Reichel, R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.27.525553 · Cited by 8
Self-citationRuiz, C. F., Ge, X., McDonnell, R., Agabiti, S. S., McQuaid, D. C., Tang, A., Kharwa, M., Goodell, J., Saavedra-Peña, R. D. M., Wing, A., et al. (2026) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-0734 · Cited by 7
Min, J., Schweizer, L., Zonderland, G., Selvanesan, B. C., Thomsen, J. H., Oldenburg, L., Bae, S.-W., Kim, B., Hernandez, S. D., Jez, G., et al. (2026) · Cancer Discovery · doi:10.1158/2159-8290.cd-25-1119 · Cited by 9
“Genetic studies estimate a median latency period of several years from the common ancestor to clinically apparent cancer (35), presenting a window to identify at-risk patients far earlier than current imaging-based approaches permit.”
Gimotty, P. A., Till, J. E., Udgata, S., Takenaka, N., Yee, S. S., Lariviere, M. J., O’Hara, M. H., Reiss, K. A., O'Dwyer, P. J., Katona, B. W., et al. (2021) · Oncotarget · doi:10.18632/oncotarget.28099 · Cited by 7
“In addition, recent studies indicate that PDAC may progress more rapidly [6] than previously appreciated [7, 8].”
BackgroundIs the Early Detection of Pancreatic Cancer Possible? It Is Good News, Bad News
Hruban, R. H. (2019) · Pancreas · doi:10.1097/mpa.0000000000001299 · Cited by 7
Self-citationClonal analysis of metachronous double biliary tract cancers
Omori, Y., Aoki, S., Ono, Y., Kokumai, T., Yoshimachi, S., Sato, H., Kusaka, A., Iseki, M., Douchi, D., Miura, T., et al. (2024) · The Journal of Pathology · doi:10.1002/path.6265 · Cited by 6
“In addition to clonal heterogeneity having been evidenced in patients with BTCs [16,17,19], individual tumors with common genetic alterations are proposed to be derived from a common founder clone, even if their phenotypes are different [21 – 24].”
BackgroundMethodInfluentialCancer metabolism challenges genomic instability and clonal evolution as therapeutic targets
Takeda, Y., Chijimatsu, R., Ofusa, K., Kobayashi, S., Doki, Y., Eguchi, H., & Ishii, H. (2022) · Cancer Science · doi:10.1111/cas.15279 · Cited by 5
Yang, S., Chen, T., Cui, M., & Hu, Y. N. (2025) · International Journal of Surgery · doi:10.1097/js9.0000000000002814 · Cited by 6
“Genomic analyses confirm high-grade PanINs as precursors to synchronous PDAC, sharing driver mutations and evolutionary trajectories [ 23 ] .”
Genomic evolution of pancreatic cancer at single-cell resolution
Zhang, H., Sashittal, P., Karnoub, E.-R. R., Jakatdar, A., Umeda, S., Hong, J., Noronha, A. M., Cardenas, A., Erakky, A., McIntyre, C. A., et al. (2026) · Nature Genetics · doi:10.1038/s41588-025-02468-9 · Cited by 5
“5a,b), corresponding to one or more KRAS -mutant clones present within the pancreatic parenchyma that was infiltrated by the main PDAC 24,29 .”
Self-citationHa, C. S. R., Müller‐Nurasyid, M., Petrera, A., Hauck, S. M., Marini, F., Bartsch, D. K., Slater, E. P., & Strauch, K. (2023) · PLoS ONE · doi:10.1371/journal.pone.0280399 · Cited by 5
Takeda, Y., Matsumoto, K., Onoyama, T., Yamashita, T., Koda, H., Hamamoto, W., Sakamoto, Y., Shimosaka, T., Kawahara, S., Seki, Y., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13091536 · Cited by 4
A conserved re-epithelialization program underlies malignancy in pancreatic ductal adenocarcinoma
Zhuo, M., Li, Y., Zhang, Y., Yang, C. R., Zou, D., Xu, W., Han, J., Wang, S., Deng, H., Pan, X., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.03.021 · Cited by 3
Tachibana, S., Mizukami, Y., Ono, Y., Sugiyama, Y., Okada, T., Kitazaki, A., Sasajima, J., Tominaga, M., Sakamoto, J., Kimura, K., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00728 · Cited by 3
“By targeting the main pancreatic ductal adenocarcinoma (PDA)related genes using multi-regional paired tumor and germline DNA sequencing, we were able to establish the evolutionary history of the emergence of ancestral tumor cells and associated subclones, one of which led to the development of discontinuous PDAs.”
BackgroundResultInfluentialClinical Relevance of Cancerization of Ducts in Resected Pancreatic Ductal Adenocarcinoma
Kinny‐Köster, B., Ahmad, Y., Pflüger, M. J., Habib, J. R., Fujikura, K., Hutchings, D., Cameron, J. L., Shubert, C. R., Lafaro, K. J., Burkhart, R. A., et al. (2024) · Pancreas · doi:10.1097/mpa.0000000000002326 · Cited by 3
“24 An additional explanation of these data was suggested by Connor and Gallinger, being that high genomic similarity among spatially unrelated lesions in the background of PDAC could be interpreted as originating from PDAC.”
BackgroundSelf-citationAnandi, L., V, Garcia, J., Ros, M., Janská, L., Liu, J., & Carmona‐Fontaine, C. (2024) · Life Science Alliance · doi:10.26508/lsa.202403053 · Cited by 2
“In addition, the initiation of metastasis is a stochastic process, and thus, when and where a metastatic clone emerges is unpredictable (Chen et al, 2009; Klein, 2009; Makohon-Moore et al, 2018).”
Yuan, Q., Chen, J., Luo, P., liu, K., Guo, F., Xu, Y., Tong, M., Xiang, H., & Shang, D. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-026-03712-8 · Cited by 2
“Importantly, oncogenic KRAS is found in over 90% of human PanIN lesions and PCs [4], and KRAS mutation in mouse acinar is sufficient to induce ADM and low-grade PanIN formation.”
Is it time to reconsider the principles of pancreatic cancer surgery?
Barreto, S. G., & Sirohi, B. (2018) · Pancreatology · doi:10.1016/j.pan.2018.12.003 · Cited by 2
A war on many fronts: cross disciplinary approaches for novel cancer treatment strategies
Herrera, A. D. P., & Ferrall‐Fairbanks, M. C. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1383676 · Cited by 2
Emerging and extensive clonal evolution in the pancreas
Makohon-Moore, A. P. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.06.011 · Cited by 2
Self-citationOkada, T., Mizukami, Y., Hayashi, A., Kawabata, H., Sato, H., Kawamoto, T., Goto, T., Taniue, K., Ono, Y., Karasaki, H., et al. (2020) · Suizo · doi:10.2958/suizo.35.302 · Cited by 2
Skip to the end: metastasis before tumorigenesis
Nobre, A. R., & Boire, A. A. (2022) · Nature Genetics · doi:10.1038/s41588-022-01228-3 · Cited by 1
Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia
Douville, C. B., Parksong, J., Molin, M. D., Graham, S., Greipp, P. T., Knudson, R. A., Curtis, S. D., Wang, Y., Dobbyn, L., Popoli, M., et al. (2026) · Science Advances · doi:10.1126/sciadv.adx7501 · Cited by 1
“Sections of frozen or FFPE tumor tissues were either macro-or microdissected and DNA purified, as described in ( 59 , 69 – 71 ).”
Self-citationEarly cellular plasticity promotes progression and dissemination in pancreatic adenocarcinoma
Innamorati, G., Malpeli, G., Giacomello, L., Salvia, R., & Wilkie, T. M. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10326-1 · Cited by 1
“Studies using single-nucleotide variants and insertions/deletions to analyze microdissected PanINs and distant PDAC lesions within the same pancreas [26] have revealed: – Distinct progeny suggesting synchronous growth.”
Wang, Y., Zhang, Y., Wang, X., Zhao, W., Li, Q., Zhou, M., Liu, Y., Yi, X., He, J. I., Li, Y. P., et al. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02712-8 · Cited by 1
“As the main subtype of PC, the PDAC’s two main precursor pathways are categorized into pancreatic intraepithelial neoplasia (PanINs) and intraductal papillary mucinous neoplasms (IPMNs) [10, 11].”
Remnant Pancreatic Cancer After Surgical Resection for Pancreatic Cancer
Miyasaka, Y., & Nakamura, M. (2022) · Springer eBooks · doi:10.1007/978-981-19-0063-1_54 · Cited by 1
Palliative treatment of pancreatic cancer
Tseimakh, A. E., Lazarev, A. F., & Shoykhet, Y. N. (2023) · Russian Journal of Oncology · doi:10.17816/onco115222 · Cited by 1
Giordano, G., Cipolletta, G., Mellone, A., Puopolo, G., Coppola, L., Santis, E. D., Forte, N. R., Napolitano, F., Caruso, F. P., Parente, P., et al. (2024) · Pancreatology · doi:10.1016/j.pan.2024.06.010 · Cited by 1
Chen, R., Sugiyama, A., Kataoka, N., Sugimoto, M., Yokoyama, S., Fukuda, A., Takaishi, S., & Seno, H. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00316 · Cited by 1
“PanIN is usually confirmed histologically as it develops into infiltrative adenocarcinoma via various steps from low grade to high grade, with gradual morphological changes (9).”
BackgroundSchäfer, H., Traulsen, A., & Sebens, S. (2019) · HepatoBiliary Surgery and Nutrition · doi:10.21037/hbsn.2019.06.03
Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor SuppressionPreprint
Barriga, F. M., Tsanov, K. M., Ho, Y.-J., Sohail, N., Zhang, A. X. W., Baslan, T., Wuest, A. N., Priore, I. S. D., Meškauskaitė, B., Livshits, G., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.08.22.504793 · Cited by 1
Self-citationMolecular and morphologic study of pancreatic cancer evolution
Noë, M. (2020) · Utrecht University Repository (Utrecht University) · doi:10.33540/3
Metadata
- Authors
- Makohon-Moore, A. P., Matsukuma, K., Zhang, M., Reiter, J. G., Gerold, J. M., Jiao, Y., Sikkema, L., Attiyeh, M. A., Yachida, S., Sandone, C., Hruban, R. H., Klimstra, D. S., Papadopoulos, N., Nowak, M. A., Kinzler, K. W., Vogelstein, B., & Iacobuzio-Donahue, C. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Davis (US)
- Johns Hopkins University (US)
- Harvard University (US)
- The University of Osaka (JP)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Nature
- Published
- 2018-09
- Volume
- 561
- Issue
- 7722
- Pages
- 201-205
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6342205
- OpenAlex
- W2888908131
- Cited by
- 120
- References
- 47
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 14 · 2023: 17 · 2022: 13 · 2021: 13 · 2020: 20 · 2019: 19 · 2018: 3
- FWCI
- 4.15
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Lustgarten Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- Rolfe Pancreatic Cancer Foundation
- Austrian Science Fund (J 3996)
- National Institutes of Health (CA062924)
- National Cancer Institute (T32CA067751, T32CA160001, F31CA180682, P50CA062924, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- pancreatic cancer, pancreatic precursor lesions, somatic mutations, clonal evolution, tumor progression, pancreatic ductal system, tumor heterogeneity, driver mutations
- MeSH terms
- Exome Sequencing, Humans, Models, Biological, Neoplasm Invasiveness, Pancreatic Ducts, Pancreatic Neoplasms, Precancerous Conditions, Time Factors, Mutagenesis, Disease Progression, Cell Lineage, Evolution, Molecular, Polymorphism, Single Nucleotide, Carcinoma, Pancreatic Ductal, INDEL Mutation
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