Animal models of xenograft-induced cachexia of patient-derived pancreatic cancer: exploring potential new biomarkers and treatment targets

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often accompanied by cachexia, a condition marked by physical decline, anorexia, and reduced quality of life. Cachexia varies in severity, categorized as precachexia, cachexia, and refractory cachexia, impacting patient survival and wellbeing. To explore cancer cachexia, we developed two experimental models using PDAC fragments from patients P08 and P12. Methods: Female BALB/c nude mice received subcutaneous transplants of PDAC xenografts from these patients. We rigorously assessed animal phenotypes, metabolism, and behavior during tumor progression to validate these cachexia models. Results: Each patient-derived xenograft (PDX) displayed a distinct cachexia profile. Mice with P12-derived PDAC exhibited mild cachexia, showing reductions in muscle (15%) and brown adipose tissue (25%) mass, and decreased activity (35%), without significant weight loss or food intake changes. In contrast, P08-derived PDAC induced severe cachexia with pronounced losses in body weight (29%), muscle (38%), cardiac muscle (27%), and brown adipose tissue (60%), coupled with sustained strength decline (51%). Both models exhibited increased pro-inflammatory cytokine expression in tumor tissues and markers associated with muscle degradation. Conclusions: Our findings highlight those mice with patient-derived PDAC xenotransplants represent robust models for studying the diverse cachexia profiles observed in patients. These models reflect the heterogeneity of PDAC cachexia and can distinguish between different stages. Importantly, they unveil potential biomarkers like IL-1β, IL-6, P2Y2 receptor, and ASS1, indicative of cachexia severity. The models highlight cachexia's complexity and underscore the importance of personalized approaches in cancer treatment.