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To examine effects of PP6 gene ( Ppp6c ) deficiency on pancreatic tumor development, we developed pancreas‐specific, tamoxifen‐inducible  C re‐mediated KP ( K RAS(G12D) plus Tr p 53‐deficient) mice (cKP mice) and crossed them with  Ppp6c flox   /   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 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia‐like features