Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-β (TGF-β) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the type II TGF-β receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras G12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras G12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras G12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras G12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras G12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.
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Pancreas-specific blockade of TGF-β signaling combined with active KRAS expression led to aggressive PDAC development with enhanced progression, metastatic potential, and invasion.
“In a study, pancreas-specific blockade of TGF-β signaling, combined with active KRAS expression, led to aggressive PDAC development with enhanced progression, metastatic potential, and invasion [86].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [86]
GEMMs combining Kras mutation with inactivation of Cdkn2a and Tp53, or with inactivation of TGFβ-SMAD4 signaling, develop invasive and metastatic PDAC, validating these tumor suppressor pathways in PDAC progression.
“GEMMs with compound mutations that combine Kras mutation with the inactivation of tumor suppressor genes Cdkn2a and Tp53, or with the inactivation of the TGFβ-SMAD4 signaling pathway in the pancreas develop invasive and metastatic PDAC (74–76), thus validating the role of these tumor suppressor pathways in PDAC progression (4).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [76]
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- Authors
- Ijichi, H., Chytil, A., Gorska, A. E., Aakre, M. E., Fujitani, Y., Fujitani, S., Wright, C. V. E., & Moses, H. L.
- Affiliations
- Vanderbilt University (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2006-11-15
- Volume
- 20
- Issue
- 22
- Pages
- 3147-3160
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1635149
- OpenAlex
- W2140946995
- Cited by
- 379
- References
- 3
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 15 · 2023: 19 · 2022: 10 · 2021: 26 · 2020: 21 · 2019: 19 · 2018: 20 · 2017: 20 · 2016: 19 · 2015: 22 · 2014: 25 · 2013: 22 · 2012: 22
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- T.J. Martell Foundation
- Uehara Memorial Foundation
- National Cancer Institute (CA 085492, R01CA085492, CA102162, R01CA102162)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- pancreatic ductal adenocarcinoma, TGF-beta signaling, TGFBR2, KRAS G12D, SMAD4, haploinsufficiency, Ras signaling, tumor progression, intraepithelial neoplasia
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Adenocarcinoma, Aging, Animals, Epithelium, Heterozygote, Mice, Inbred C57BL, Mutation, Neoplasm Invasiveness, Pancreas, Pancreatic Neoplasms, Genes, ras, Transcription Factors, Tumor Cells, Cultured, Signal Transduction, Gene Expression, Transforming Growth Factor beta, Stromal Cells, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Receptors, Transforming Growth Factor beta, Mice, Knockout, Disease Progression, Carcinoma, Pancreatic Ductal, Intercellular Signaling Peptides and Proteins, Mice, Connective Tissue Growth Factor
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