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At 30\u00a0days, a comparative analysis of genes commonly altered in homozygous versus WT <jats:italic>Ppp6c<\/jats:italic> cKP mice revealed enhanced activation of Erk and NF\u03baB pathways in homozygotes. By 80\u00a0days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of <jats:italic>Ppp6c<\/jats:italic> homozygous relative to heterozygous or WT cKP mice. <jats:italic>Ppp6c<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial\u2013mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer\u2010specific glycolytic metabolism in <jats:italic>Ppp6c<\/jats:italic>\u2010deficient cKP mice and the increased expression of inflammatory cytokines. Individual <jats:italic>Ppp6c<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)\u2010\u03b1 and IL\u20106\u00a0levels, suggestive of systemic inflammation. Overall, <jats:italic>Ppp6c<\/jats:italic> deficiency in the presence of <jats:italic>K<\/jats:italic>\u2010<jats:italic>ras<\/jats:italic> mutations and <jats:italic>Trp53<\/jats:italic>\u00a0gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that <jats:italic>Ppp6c<\/jats:italic> suppresses mouse pancreatic carcinogenesis and supports the use of <jats:italic>Ppp6c<\/jats:italic>\u2010deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer.<\/jats:p>","DOI":"10.1111\/cas.15315","type":"journal-article","created":{"date-parts":[[2022,3,5]],"date-time":"2022-03-05T12:28:41Z","timestamp":1646483321000},"page":"1613-1624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia\u2010like features"],"prefix":"10.1111","volume":"113","author":[{"given":"Katsuya","family":"Fukui","sequence":"first","affiliation":[{"name":"Division of Cancer Chemotherapy Miyagi Cancer Center Research Institute  Natori Japan"},{"name":"Division of Cancer Molecular Biology Tohoku University Graduate School 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