Cachexia‐induced reprogramming of visceral organ metabolism by human pancreatic cancer xenografts

Pancreatic cancer patients with cachexia experience functional changes in visceral organs. To further understand these functional changes, here, for the first time, we characterized metabolic changes in the spleen, liver, pancreas, lungs, heart, and kidneys induced by human pancreatic cancer xenografts. These studies identify the commonality and consequences of cachexia-induced visceral organ metabolic dysregulation. The heart, kidneys, liver, lungs, pancreas, and spleen from euthanized non-tumor-bearing control mice and from cachexia-inducing Pa04C and non-cachexia-inducing Panc1 tumor-bearing mice (n = 8-10 per group) were metabolically characterized with 1H magnetic resonance spectroscopy. All visceral organs, with the exception of lungs, exhibited significant weight reduction in cachectic Pa04C mice relative to normal and non-cachectic Panc1 mice. A significant reduction (p ≤ .0166) of organ metabolites ranging from the amino acids leucine, isoleucine, valine, alanine, lysine, arginine, asparagine, glutamate, glutamine, aspartate, glycine, tyrosine, and phenylalanine, along with glucose, lactate, creatine, choline, and fumarate, depending upon the visceral organ, was observed in cachectic Pa04C mice compared to normal mice. The highest number of metabolites was reduced in the spleen, followed by the kidneys, lungs, and liver. The metabolic changes identified can lead to negative consequences in organ function by impacting pathways involved in tissue regeneration and resolving inflammation at the cellular level in cachectic mice. These results highlight the visceral organ metabolic reprogramming that can occur with cancer-induced cachexia, an understanding of which can identify noninvasive biomarkers and metabolic interventions to reduce morbidity and mortality from pancreatic cancer.