Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Nabeel
N
Bardeesy
Andrew J
AJ
Aguirre
Gerald C
GC
Chu
Kuang-Hung
KH
Cheng
Lyle V
LV
Lopez
Aram F
AF
Hezel
Bin
B
Feng
Cameron
C
Brennan
Ralph
R
Weissleder
Umar
U
Mahmood
Douglas
D
Hanahan
Mark S
MS
Redston
Lynda
L
Chin
Ronald A
RA
Depinho
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D016158:Genes, p53; D006720:Homozygote; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53