Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia

Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand the mechanisms underlying cachexia. One such model is the <i>Kras</i>^LSL-G12D, <i>Ptf1a</i>^Cre-ER/+, <i>Pten</i>^flox/flox (KPP) model, which utilizes an inducible Cre recombinase to initiate tumor development by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 wk of age. However, mice are rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to the slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 wk of age (KPP10). Given the expanding evidence of sexual dimorphisms in cancer cachexia, we utilized both male and female mice to assess potential sex differences. Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared with nontumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that survival was significantly shorter in female KPP10 mice compared with KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.<b>NEW & NOTEWORTHY</b> Although male mice experience greater relative body weight losses, similar skeletal muscle and adipose tissue wasting occurs between male and female mice in the <i>Kras</i>^LSL-G12D, <i>Ptf1a</i>^Cre-ER/+, <i>Pten</i>^flox/flox (KPP) model of pancreatic-cancer-induced cachexia. Greater weight loss in males may be related to longer survival. However, differences in tamoxifen dose relative to body weight may have accelerated tumor formation in female mice and, therefore, may be a relevant consideration for inducible tumor models.