Characterization of genetic subclonal evolution in pancreatic cancer mouse models

Abstract

The KPC mouse model, driven by the Kras and Trp53 transgenes, is well regarded for faithful recapitulation of human pancreatic cancer biology. However, the extent that this model recapitulates the subclonal evolution of this tumor type is unknown. Here we report evidence of continuing subclonal evolution after tumor initiation that largely reflect copy number alterations that target cellular processes of established significance in human pancreatic cancer. The evolutionary trajectories of the mouse tumors show both linear and branching patterns as well as clonal mixing. We propose the KPC model and derivatives have unexplored utility as a functional system to model the mechanisms and modifiers of tumor evolution.

Current methods in translational cancer research

“…Other modifications in DNA damage response genes (Msh3), and genes involved in cellular recovery to DNA damage (Mastl) were also noted [96]. This group also discovered an unrecognized role for the gene Nlrp1b (part of a family of immune pattern recognition receptors) that was found to have undergone focal homozygous deletion in three mice (KPC8, KPC9, and KPTC26) [96][97][98]. Nlrp1b is also somatically altered in human pancreatic cancers.…”

“…Niknarfs et al used transgenic GEMMs to characterize clonal evolution in pancreatic cancer [96]. The two GEMMs, known as KPC (LSL-Kras G 1 2 D / + ; LSL-Trp53 R172H/+ ; Pdx1-Cre) and KPTC (LSL-KRASG12D/ + ; LSL-Trp53R172H/ + ; Tgfbr2flox/ + ; Ptf1aCre/ + ) are conditional mice that when bred with cre-recombinase-expressing mice, lead to expression of active mutant Kras, and loss of p53 (by means of a dominant negative mutation) [96]. These mice closely mimic the histopathology and clinical features of PDAC and are more biologically relevant models for studying clonal evolution and tumor heterogeneity [96].…”

“…The two GEMMs, known as KPC (LSL-Kras G 1 2 D / + ; LSL-Trp53 R172H/+ ; Pdx1-Cre) and KPTC (LSL-KRASG12D/ + ; LSL-Trp53R172H/ + ; Tgfbr2flox/ + ; Ptf1aCre/ + ) are conditional mice that when bred with cre-recombinase-expressing mice, lead to expression of active mutant Kras, and loss of p53 (by means of a dominant negative mutation) [96]. These mice closely mimic the histopathology and clinical features of PDAC and are more biologically relevant models for studying clonal evolution and tumor heterogeneity [96]. Based on their results, these authors concluded that KPC and KPTC mice accumulate sub-clonal somatic mutations as measured by copy number alterations in essential PDAC pathways including chromosomes containing the Cdkn2a gene (chr4), Tgfbr2 gene (chr9), and Trp53 (chr11) [96].…”

“…These mice closely mimic the histopathology and clinical features of PDAC and are more biologically relevant models for studying clonal evolution and tumor heterogeneity [96]. Based on their results, these authors concluded that KPC and KPTC mice accumulate sub-clonal somatic mutations as measured by copy number alterations in essential PDAC pathways including chromosomes containing the Cdkn2a gene (chr4), Tgfbr2 gene (chr9), and Trp53 (chr11) [96]. Other modifications in DNA damage response genes (Msh3), and genes involved in cellular recovery to DNA damage (Mastl) were also noted [96].…”

“…Based on their results, these authors concluded that KPC and KPTC mice accumulate sub-clonal somatic mutations as measured by copy number alterations in essential PDAC pathways including chromosomes containing the Cdkn2a gene (chr4), Tgfbr2 gene (chr9), and Trp53 (chr11) [96]. Other modifications in DNA damage response genes (Msh3), and genes involved in cellular recovery to DNA damage (Mastl) were also noted [96]. This group also discovered an unrecognized role for the gene Nlrp1b (part of a family of immune pattern recognition receptors) that was found to have undergone focal homozygous deletion in three mice (KPC8, KPC9, and KPTC26) [96][97][98].…”