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 (Trp53R172H/+), CDKN2A (Ink4flox/+) 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-KrasG12D; Ink4flox/flox; Ptf1/p48-Cre mice (KIC) (89 vs 62 days) and shorter than that of KRAS (KrasG12D), TP53 (Trp53R172H/+) 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.
Highlights
Pancreatic cancer (PC) is a uniformly lethal malignancy with extremely poor outcomes [1]
In 1 KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre (KPIC) mouse, the 2 hind legs were completely paralyzed at 13 weeks, and histology revealed a tumor in the spinal cord (Figs not shown)
The histology showed that 3/5 mice developed typical ductal adenocarcinoma, and 2/5 mice exhibited high-grade panIN; both the adenocarcinoma and high-grade panIN were rich in desmoplastic stroma, which are similar to well-differentiated adenocarcinoma in KrasG12D; Ink4flox/flox; Ptf1/p48-Cre mice (KIC) (Fig 1C and 1D)
Summary
The progression of PC is a multistep process, and the tumor accumulates different tumorigenic mutations during the different stages [2]. An applicable model for local invasive and metastatic pancreatic cancer subsequently inactivates the tumor suppressor genes p16Ink4a, p14ARF, TP53, and/or SMAD4 [2,3,4]. Human PC often harbors high frequencies of multiple mutations, including KRAS (>90%), p16Ink4a (>60%), p53 (>50%) and SMAD4 (50%) gene mutations [1, 5]. GEMMs provide a powerful tool to dissect the roles of these mutations in PC progression but reveal the synergistic effects of these mutations in disease trajectory, providing a model to test chemotherapeutic drugs in preclinical trials [6, 7]
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