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LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer

Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (G...

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Autores principales: Ma, Lixiang, Saiyin, Hexige
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419507/
https://www.ncbi.nlm.nih.gov/pubmed/28475592
http://dx.doi.org/10.1371/journal.pone.0176844
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author Ma, Lixiang
Saiyin, Hexige
author_facet Ma, Lixiang
Saiyin, Hexige
author_sort Ma, Lixiang
collection PubMed
description Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC. However, the effect of the combination of TP53, CDKN2A and KRAS mutations on the trajectory of PC progression is unknown. Here, we report a GEMM that harbors KRAS (Kras(G12D)), TP53 (Trp53(R172H/+)), CDKN2A (Ink4(flox/+)) and Ptf1/p48-Cre (KPIC) mutations. Histopathology showed that KPIC mice developed adenocarcinoma that strongly resembled the pathology of human PC, characterized by rich desmoplastic stroma and low microvascularity. The median survival of KPIC mice was longer than that of LSL-Kras(G12D); Ink4(flox/flox); Ptf1/p48-Cre mice (KIC) (89 vs 62 days) and shorter than that of KRAS (Kras(G12D)), TP53 (Trp53(R172H/+)) and Ptf1/p48-Cre (KPC) mice. Moreover, the neoplastic cells of KPIC mice were epithelial, highly proliferative tumor cells that exhibited ERK and MAPK pathway activation and high glucose uptake. Isolated neoplastic cells from spontaneous KPIC tumors showed all molecular profiles and cellular behaviors of spontaneous KPIC tumors, including epithelial-mesenchymal transition (EMT) under drug stress as well as tumorigenic, metastatic and invasive abilities in immunocompetent mice. Furthermore, orthotopic and metastatic tumors of KPIC cells almost recapitulated the pathology of spontaneous KPIC tumors. These data show that in addition to spontaneous KPIC tumors, KPIC cells are a valuable tool for preclinical studies of locally invasive and metastatic PC.
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spelling pubmed-54195072017-05-14 LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer Ma, Lixiang Saiyin, Hexige PLoS One Research Article Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC. However, the effect of the combination of TP53, CDKN2A and KRAS mutations on the trajectory of PC progression is unknown. Here, we report a GEMM that harbors KRAS (Kras(G12D)), TP53 (Trp53(R172H/+)), CDKN2A (Ink4(flox/+)) and Ptf1/p48-Cre (KPIC) mutations. Histopathology showed that KPIC mice developed adenocarcinoma that strongly resembled the pathology of human PC, characterized by rich desmoplastic stroma and low microvascularity. The median survival of KPIC mice was longer than that of LSL-Kras(G12D); Ink4(flox/flox); Ptf1/p48-Cre mice (KIC) (89 vs 62 days) and shorter than that of KRAS (Kras(G12D)), TP53 (Trp53(R172H/+)) and Ptf1/p48-Cre (KPC) mice. Moreover, the neoplastic cells of KPIC mice were epithelial, highly proliferative tumor cells that exhibited ERK and MAPK pathway activation and high glucose uptake. Isolated neoplastic cells from spontaneous KPIC tumors showed all molecular profiles and cellular behaviors of spontaneous KPIC tumors, including epithelial-mesenchymal transition (EMT) under drug stress as well as tumorigenic, metastatic and invasive abilities in immunocompetent mice. Furthermore, orthotopic and metastatic tumors of KPIC cells almost recapitulated the pathology of spontaneous KPIC tumors. These data show that in addition to spontaneous KPIC tumors, KPIC cells are a valuable tool for preclinical studies of locally invasive and metastatic PC. Public Library of Science 2017-05-05 /pmc/articles/PMC5419507/ /pubmed/28475592 http://dx.doi.org/10.1371/journal.pone.0176844 Text en © 2017 Ma, Saiyin http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ma, Lixiang
Saiyin, Hexige
LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title_full LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title_fullStr LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title_full_unstemmed LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title_short LSL-Kras(G12D); LSL-Trp53(R172H/+); Ink4(flox/+); Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
title_sort lsl-kras(g12d); lsl-trp53(r172h/+); ink4(flox/+); ptf1/p48-cre mice are an applicable model for locally invasive and metastatic pancreatic cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419507/
https://www.ncbi.nlm.nih.gov/pubmed/28475592
http://dx.doi.org/10.1371/journal.pone.0176844
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