Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer
Open accessAbstract
SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC—alone or in combination with PDAC-relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS G12D allele, SMAD4 deficiency enabled rapid progression of KRAS G12D -initiated neoplasms. While KRAS G12D alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS G12D and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS G12D INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor-β (TGF-β) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-β-induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS G12D -initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF-β-dependent growth.
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Mice with SMAD4 deficiency do not exhibit abnormalities in pancreas structure or physiology.
“Interestingly, mice with SMAD4 deficiency did not exhibit abnormalities in pancreas structure or physiology.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [65]
When combined with oncogenic KrasG12D mutation, Smad4 deletion dramatically accelerates development of pancreatic tumors, leading to significant reduction in survival.
“However, when combined with the oncogenic KrasG12D mutation, Smad4 deletion dramatically accelerated the development of pancreatic tumors, leading to a significant reduction in survival [65].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [65]
Combined expression of oncogenic Kras with deletion or loss of function of Trp53, Cdkn2a, or Smad4 in mouse pancreas readily leads to invasive PDAC.
“combined expression of oncogenic Kras coupled with the deletion or loss of function of Trp53, Cdkn2a, or Smad4 in the pancreas of mice readily leads to invasive PDAC29–32.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [29]
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Cites
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- Authors
- Bardeesy, N., Cheng, K.-H., Berger, J. H., Chu, G. C., Pahler, J., Olson, P., Hezel, A. F., Horner, J., Lauwers, G. Y., Hanahan, D., & DePinho, R. A.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- University of California, San Francisco (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2006-11-15
- Volume
- 20
- Issue
- 22
- Pages
- 3130-3146
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1635148
- OpenAlex
- W2100801124
- Cited by
- 674
- References
- 6
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 30 · 2023: 22 · 2022: 33 · 2021: 45 · 2020: 35 · 2019: 40 · 2018: 36 · 2017: 45 · 2016: 36 · 2015: 46 · 2014: 36 · 2013: 41 · 2012: 38
- 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
- Ellison Medical Foundation
- Samuel Waxman Cancer Research Foundation
- National Institutes of Health (NIH K01)
- Harvard Stem Cell Institute
- National Cancer Institute (K01CA104647, 5U01CA84313-08, U01CA084313, P01CA117969)
- 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
- SMAD4, pancreatic ductal adenocarcinoma, pancreatic development, KRAS G12D, Ink4a/Arf, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, tumor suppressor, epithelial-mesenchymal transition, TGF-beta, pancreatic cancer progression, pancreatic epithelium
- MeSH terms
- Alleles, Animals, Cell Differentiation, Pancreas, Pancreatic Neoplasms, Phenotype, Genes, ras, Transforming Growth Factor beta, Gene Deletion, Disease Progression, Cyclin-Dependent Kinase Inhibitor p16, Carcinoma, Pancreatic Ductal, Tumor Suppressor Protein p14ARF, Cell Line, Tumor, Mice, Smad4 Protein
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