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

Abstract

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 (KrasG12D), in combination with either p53 mutation by knock-in strategy (Trp53R172H) or p53 loss by conditional knockout (Trp53cKO) strategy, in pancreatic cell lineages. However, the systematic comparison of the tumor microenvironment between KrasG12D; Trp53R172H (KPmut) mouse models and KrasG12D; Trp53cKO (KPloss) 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 KPmut mouse models and KPloss 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 KPmut and KPloss mouse models, revealing the effects of p53 mutation and p53 loss on oncogenic KRAS-driven pancreatic tumor progression.