ArticleProceedings of the National Academy of Sciences of the United States of America2006
Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 366 papers, 1 of them a synthesis that pooled it.
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366 citing papers in PubMed, 1 synthesis or guideline pooled it, 580 citations in OpenAlex.
- PGC1α-Mediated Metabolic Reprogramming Drives the Stemness of Pancreatic Precursor Lesions.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Pooled it
- Article
- Genotype-Informed Whole-Animal Kinome Screening Reveals Shared Kinase Vulnerabilities Across Driver Contexts in PDAC.Cancer science · 2026Article
- Blocking L-carnitine synthesis by meldonium prolongs the survival in mice with pancreatic cancer.iScience · 2026Article
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- Iron overload suppresses LKB1 and induces IL36G anti-tumor immunity in PDAC metastasis.Science advances · 2026Article
- Inactivation of CDKN2AARF Promotes p53-Independent Remodeling of the PDAC Tumor Microenvironment.Cancer research · 2026Article
- The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion.Developmental cell · 2026Article
- Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation.Developmental cell · 2026Article
- NF-κB inducing kinase (NIK) deletion accelerates KRAS-driven pancreatic cancer in association with tumor microenvironment remodeling.Cell death & disease · 2026Article
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- KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.Cancer research · 2026Article
- Genomic evolution of pancreatic cancer at single-cell resolution.Nature genetics · 2026Article
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- Efficient and multiplexed somatic genome editing with Cas12a mice.Nature biomedical engineering · 2025Article
- An alternative route for β-hydroxybutyrate metabolism supports cytosolic acetyl-CoA synthesis in cancer cells.Nature metabolism · 2025Article
- Loss of Sorting Nexin 10 Accelerates KRAS-Induced Pancreatic Tumorigenesis.Cancer research communications · 2025Article
- A RAS(ON) Multi-Selective Inhibitor Combination Therapy Triggers Long-term Tumor Control through Senescence-Associated Tumor-Immune Equilibrium in Pancreatic Ductal Adenocarcinoma.Cancer discovery · 2025Article
- Article
- HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity.Nature communications · 2025Article
306 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 8 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Activating KRAS mutations and p16(Ink4a) inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras(G12D) initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16(Ink4a)/p19(Arf)) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16(Ink4a) in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16(Ink4a), p19(Arf), and/or p53 in the Kras(G12D) model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16(Ink4a), the latter with intact germ-line p53 and p19(Arf) sequences. Additionally, Kras(G12D) in the context of heterozygosity either for p53 plus p16(Ink4a) or for p16(Ink4a)/p19(Arf) produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16(Ink4a)/p19(Arf). Tumors from the double-heterozygous cohorts showed frequent p16(Ink4a) inactivation and loss of either p53 or p19(Arf). Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16(Ink4a)/p19(Arf) mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16(Ink4a) and the p19(ARF)-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.
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