LSL-Kras flox/+mice are an applicable model for locally invasive and metastatic pancreatic cancer

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Abstract

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 (KrasG12D), 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 ; 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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APA

Ma, L., & Saiyin, H. (2017). LSL-Kras flox/+mice are an applicable model for locally invasive and metastatic pancreatic cancer. PLoS ONE, 12(5). https://doi.org/10.1371/journal.pone.0176844

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