Disruption of p16 and Activation of Kras in Pancreas Increase Ductal Adenocarcinoma Formation and Metastasis in vivo
Open accessAbstract
Wanglong Qiu 1 , Fikret Sahin 3,4 , Christine A. Iacobuzio-Donahue 3 , Dario Garcia-Carracedo 1 , Wendy M. Wang 1 , Chia-Yu Kuo 1 , Doris Chen 1 , Dan E. Arking 5 , Andrew M. Lowy 6 , Ralph H. Hruban 3 , Helen E. Remotti 2 , and Gloria H. Su 1,2* 1 The Departments of Otolaryngology and Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032 2 Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032 3 The Sol Goldman Pancreatic Cancer research Center, Department of Pathology, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205 4 Microbiology Department, School of Medicine, Ankara University, Turkey 5 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 6 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0987 Received: November 16, 2011; Accepted: November 22, 2011; Published: November 23, 2011; Keywords: p16, LOH at Kras, pancreatic cancer, metastasis, mouse model, conditional knock-out, target therapy Correspondence: Dr. Su, email: // // Abstract Inactivation of tumor suppressor gene p16/INK4A and oncogenic activation of KRAS occur in almost all pancreatic cancers. To better understand the roles of p16 in pancreatic tumorigenesis, we created a conditional p16 knockout mouse line ( p16 flox/flox ) , in which p16 is specifically disrupted in a tissue-specific manner without affecting p19/ARF expression. p16 flox/flox ; LSL- Kras G12D ; Pdx1-Cre mice developed the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma (PDA), and metastases were observed in all the mice. Here we report a mouse model that simulates human pancreatic tumorigenesis at both genetic and histologic levels and is ideal for studies of metastasis. During the progression from primary tumors to metastases, the wild-type allele of Kras was progressively lost (loss of heterozygosity at Kras or LOH at Kras ) in p16 flox/flox ; LSL- Kras G12D ; Pdx1-Cre mice. These observations suggest a role for Kras beyond tumor initiation. In vitro assays performed with cancer cell lines derived from primary pancreatic tumors of these mice showed that cancer cells with LOH at Kras exhibited more aggressive phenotypes than those retained the wild-type Kras allele, indicating that LOH at Kras can provide cancer cells functional growth advantages and promote metastasis. Increased LOH at KRAS was also observed in progression of human pancreatic primary tumors to metastases, again supporting a role for the KRAS gene in cancer metastasis. This finding has potential translational implications- future KRAS target therapies may need to consider targeting oncogenic KRAS specifically without inhibiting wild-type KRAS function.
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p16 inactivation alone did not initiate tumorigenesis, but combined with KRAS activation, it significantly accelerated tumor progression and metastasis, closely resembling human PDAC.
“The results demonstrated that while p16 inactivation alone did not initiate tumorigenesis, combined with KRAS activation, it significantly accelerated tumor progression and metastasis, closely resembling human pancreatic ductal adenocarcinoma.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [90]
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 [32]
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Self-citation
- Authors
- Qiu, W., Sahin, F., Iacobuzio-Donahue, C. A., Garcia-Carracedo, D., Wang, W. M., Kuo, C.-Y., Chen, D., Arking, D. E., Lowy, A. M., Hruban, R. H., Remotti, H. E., & Su, G. H.
- Affiliations
- Columbia University Irving Medical Center (US)
- Johns Hopkins University (US)
- The Sol Goldman Pancreatic Cancer research Center, Department of Pathology, The Johns Hopkins University Medical Institutions, Baltimore, MD 21205
- The Departments of Otolaryngology and Head and Neck Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032
- University of California San Diego (US)
- Columbia University (US)
- Corresponding author
- Su, Gloria H.
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2011-11-23
- Volume
- 2
- Issue
- 11
- Pages
- 862-873
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC3259996
- OpenAlex
- W2106755467
- Cited by
- 99
- References
- 35
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 8 · 2020: 8 · 2019: 6 · 2018: 14 · 2017: 4 · 2016: 6 · 2015: 4 · 2014: 8 · 2013: 9 · 2012: 9
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Lustgarten Foundation
- Johns Hopkins University
- Rolfe Pancreatic Cancer Foundation
- National Cancer Institute (R01CA155620, R56CA109525, K01CA095434, R01CA109525, CA95434)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- p16INK4a, KRAS G12D, pancreatic ductal adenocarcinoma, pancreatic cancer metastasis, pancreatic intraepithelial neoplasia, conditional knockout mouse model, Pdx1-Cre, tumor suppressor inactivation, p19ARF, tumor progression, mouse model
- MeSH terms
- Animals, Disease Models, Animal, Enzyme Activation, Humans, Neoplasm Metastasis, Pancreatic Neoplasms, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Mice, Knockout, ras Proteins, Loss of Heterozygosity, Genes, p16, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice
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