Deletion of Tumor‐derived IL‐6 Maintains Muscle Mass and Attenuates Lipolysis with Evidence for soluble IL‐6Rα as a Driver of Pancreatic Cancer Cachexia

Abstract

Cachexia, or weight loss in cancer, significantly increases morbidity and mortality and >85% of patients with pancreatic ductal adenocarcinoma (PDAC) will suffer from and die of cachexia. Interleukin‐6 (IL‐6) is increased in the blood of patients with PDAC and correlates with weight loss and cachexia severity. IL‐6 has been well documented and has been shown to directly induce muscle and fat wasting. IL‐6 activates signal transduction by first binding with the IL‐6rα via classical (membrane bound receptor) or trans‐signaling (soluble receptor) and then the IL‐6/IL‐6rα complex binds to the ubiquitously expressed glycoprotein 130 (gp130) on cell membranes. Importantly, previous studies suggest IL‐6 trans‐signaling promotes systemic inflammation in some diseases. This study aims to investigate the effects of tumor‐derived IL‐6 on cachexia and soluble IL‐6rα expression in plasma, fat, and skeletal muscle of mice with PDAC.We utilized a murine model of PDAC cachexia using orthotopic injection of tumor cells isolated from the genetic PDAC model LSL‐KrasG12D:LSL‐Trp53R172H:Pdx1‐Cre (KPC). To determine the role of tumor‐cell‐derived IL6 in PDAC cachexia, the Il6 gene in KPC cells was mutated using CRISPR/Cas9 to induce loss of expression.Results showed animals bearing KPC tumors had higher mean plasma IL‐6 versus KPC IL‐6−/− tumor and no tumor (WT) mice (291,159, 2 pg/mL respectively; p<0.05). Both KPC and KPC IL‐6−/− tumor mice had significant losses of epididymal fat mass versus WT animals (−81% and −37% respectively; p<0.002) however; KPC IL‐6−/− tumor mice had attenuation of fat loss versus KPC tumor mice. KPC tumor mice had increased loss of muscle mass (Quadriceps −21.2%, Tibialis −18.9%, Gastrocnemius −16.7%, Heart −26%; p<0.05) versus KPC IL‐6−/− tumor and WT mice. Analysis of IL‐6rα levels in plasma showed significant increases in KPC tumor mice versus WT mice (12.69 vs 0.776 ng/mL; p< 0.01) and between KPC tumor vs KPC IL‐6−/− tumor mice (12.69 vs 1.68 ng/mL; p< 0.01). No differences in plasma IL‐6rα was measured between KPC IL‐6−/− tumor and WT mice. IL‐6rα protein expression was increased in adipose tissue of KPC tumor mice versus KPC IL‐6−/− tumor and WT mice. IL‐6rα protein expression was not different in the skeletal muscle between the groups. Interestingly, RNA sequencing analysis of fat and skeletal muscle showed a significant increase (+36.8‐fold; p=5.14E‐42) in IL‐6rα reads in the skeletal muscle of KPC tumor mice versus the other groups while no difference in IL‐6rα reads was observed in adipose tissue between groups. Finally, KPC tumor mice had decreased survival compared to KPC IL‐6−/− tumor mice (Median survival: 17 vs 24 days respectively; p<0.002). Taken together, these results suggest inhibiting tumor‐derived IL‐6 reduces circulating levels of IL‐6 and IL‐6rα, which is associated with increased survival and a reduction in fat wasting and cachexiogenic potential of the tumor.Support or Funding InformationThis work was funded in part by grants to TZ from NIH (grants R01CA122596, R01CA194593, and R01GM092758)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.