Single-Cell Analysis Differentiates the Effects of p53 Mutation and p53 Loss on Cell Compositions of Oncogenic Kras-Driven Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignant disease with a dismal prognosis. In the past decades, a plethora of genetically engineered mouse models (GEMMs) with autochthonous pancreatic tumor development have greatly facilitated studies of pancreatic cancer. Commonly used GEMMs of PDAC often harbor the oncogenic KRAS driver mutation ( Kras G12D ), in combination with either p53 mutation by knock-in strategy ( Trp53 R172H ) or p53 loss by conditional knockout ( Trp53 cKO ) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between Kras G12D ; Trp53 R172H (KP mut ) mouse models and Kras G12D ; Trp53 cKO (KP loss ) mouse models is still lacking. In this study, we conducted cross-dataset single-cell RNA-sequencing (scRNA-seq) analyses to compare the pancreatic tumor microenvironment from KP mut mouse models and KP loss mouse models, especially focusing on the cell compositions and transcriptomic phenotypes of major cell types including cancer cells, B cells, T cells, granulocytes, myeloid cells, cancer-associated fibroblasts, and endothelial cells. We identified the similarities and differences between KP mut and KP loss mouse models, revealing the effects of p53 mutation and p53 loss on oncogenic KRAS-driven pancreatic tumor progression.