Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.
To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion-hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.
Hingorani
Sunil R
SR
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. srhingo@mail.med.upenn.edu
Wang
Lifu
L
Multani
Asha S
AS
Combs
Chelsea
C
Deramaudt
Therese B
TB
Hruban
Ralph H
RH
Rustgi
Anil K
AK
Chang
Sandy
S
Tuveson
David A
DA
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018385:Centrosome / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics*; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D018450:Disease Progression; D015870:Gene Expression / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D018739:Oncogene Proteins v-erbB / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D016615:Telomere / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics*
D015820:Cadherins; D018398:Homeodomain Proteins; D018739:Oncogene Proteins v-erbB; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C084010:pancreatic and duodenal homeobox 1 protein; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins