PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia‐like features

To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas‐specific, tamoxifen‐inducible Cre‐mediated KP (KRAS(G12D) plus Trp53‐deficient) mice (cKP mice) and crossed them with Ppp6cflox/flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild‐type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c−/− tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial–mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer‐specific glycolytic metabolism in Ppp6c‐deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c−/− cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)‐α and IL‐6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K‐ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c‐deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer. PP6 gene (Ppp6c) deficiency in the presence of K‐ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis in mice with generalized cachexia and early death. These mice should serve as a useful model in which to elucidate the mechanisms underlying cachexia associated with pancreatic cancer and for developing therapeutic interventions. This study is the first evidence that Ppp6c functions as a tumor suppressor in mouse pancreatic carcinogenesis.