LSL-KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre mice are an applicable model for locally invasive and metastatic pancreatic cancer

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.

Basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancer

“…This finding suggests that the growth and maintenance of basal microvilli might rely on blood flow. We also discovered basal microvilli in KRAS ‐mutated autochthonous pancreatic cancers of mice but not in orthotopic pancreatic cancers of mice [11,12,29]. However, the sizes of these tumors in mice are far smaller than those in human cancers.…”

The physiological characteristics of the basal microvilli microvessels in pancreatic cancers

“…To see if the microvasculature in the PCs of KIC presents basal microvilli, we have stained the PCs of KIC with a CD34 antibody. Similar to the microvasculature of human pancreatic cancers, autochthonous KPC, and KPIC tumors, 11,23 the microvasculature in KIC tumors also presents basal microvilli (Figure 2A). Consistent with the characteristics of human basal microvilli microvasculature, 11 we observed that the basal microvilli microvasculature in both KPC and KIC tumors has a lower level of VEGFR2 and pVEGFR2 (Y966) when compared to the microvessels in the near‐normal tissue (Figure 2B,C; Figure ).…”

“…Basal microvilli microvasculature exists in murine autochthonous PCs that harbor the KRAS mutation but not xenograft or orthotopic tumors 11,23 . These findings provide us with a limited tool to study the nutrient trafficking and blood flow of basal microvilli microvessels in PCs.…”

The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities

“…[92, 93, 94, 95, 96, 97, 98] Recent study shows that LSL-KrasG12D; LSL-Trp53R172H/+; Ink4flox/+; Ptf1/p48-Cre mouse model with multiple mutations is a more applicable model for preclinical investigation of locally invasive and metastatic pancreatic cancer. [99] The activated KRAS together with other gene mutations in pancreatic cells promotes PanINs to progress to invasive pancreatic cancers, making the models more relative to clinical pancreatic cancer. However, the GEMMs harbor same mutations in all pancreatic cells and they are homogeneous.…”