Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma
Open accessAbstract
Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
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Cerulein-induced pancreatitis, which damages acinar cells, did not promote KRAS-mediated ductal-lineage tumorigenesis.
“This was not observed in the context of damage through cerulein-induced pancreatitis118, which drives inflammation through damage of acinar cells.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [118]
Deletion of Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.
“Deletion of the ductal progenitor gene Sox9 prevented KRAS-driven transformation, while Sox9 overexpression accelerated PanIN development.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [118]
In a direct comparison, oncogenic KRAS promoted adult acinar cells to generate neoplastic lesions at a frequency over 100-fold higher than ductal cells.
“The first direct comparison using adult acinar vs. ductal expression of oncogenic KRAS demonstrated that KRAS promotes acinar cells to generate neoplastic lesions at a frequency over a hundred-fold higher than ductal cells118.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [118]
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Self-citationExtracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells
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Self-citation
- Authors
- 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., Hebrok, M., & Sander, M.
- Affiliations
- University of California San Diego (US)
- University of California, San Francisco (US)
- Vanderbilt University (US)
- Kyoto University (JP)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Hebrok, Matthias
- Sander, Maike
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 22
- Issue
- 6
- Pages
- 737-750
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3568632
- OpenAlex
- W1993913862
- Cited by
- 697
- References
- 59
- Citations by year
- 2026: 33 · 2025: 44 · 2024: 45 · 2023: 68 · 2022: 51 · 2021: 69 · 2020: 56 · 2019: 53 · 2018: 50 · 2017: 56 · 2016: 47 · 2015: 52 · 2014: 43 · 2013: 28 · 2012: 2
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1dp2od002420-01)
- National Cancer Institute (P30-CA-23100, F32CA136124, R01CA112537, P30CA023100, T32CA121938)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078803, P30DK063720)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- pancreatic ductal adenocarcinoma, tumor origin, SOX9, KRAS mutation, precancerous lesions, centroacinar cells, pancreatic acinar cells, oncogenic transformation, pancreatic stem cells, lineage tracing
- MeSH terms
- Humans, Metaplasia, Mutation, Pancreatic Neoplasms, Precancerous Conditions, Genes, ras, Carcinoma, Pancreatic Ductal, SOX9 Transcription Factor, Acinar Cells
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