Tumor, Fat and Skeletal Muscle Crosstalk via IL-6R Trans-Signaling Mediates Pancreatic Cancer Cachexia

Abstract

Cachexia, the involuntary loss of fat and muscle is associated with pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with cachexia severity and reduced survival in patients. IL-6 in cancer is well documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL- 6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had reduced cachexia, with attenuated fat loss and no significant muscle loss, and longer survival versus KPC controls. Only KPC tumor-bearing mice had significant myosteatosis, aberrant branched chain amino acid and fatty acid metabolism, and reduced pyruvate entry into the TCA-cycle, determined by increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle. Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing mice had increased muscle PKCθ activation, and PKCθ is known to regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had reduced cachexia and maintained muscle mass and force production versus wild type tumor-bearing mice. Together these data implicate progressive signaling mechanisms whereby tumor-derived IL-6 is associated with increased muscle IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ activation, ultimately increasing cachexia severity in PDAC.