Abstract 2175: Tumor-derived IL-6 impairs hepatic adaptive response to undernutrition in pancreatic cancer cachexia
Authors: Arneson-Wissink Paige C. , Mendez Heike , Pelz Katherine , Dickie Jessica , Zhu Xinxia , Olson Brennan , Marks Daniel L. , Grossberg Aaron J. 
Published: June 2022

Purpose/Objectives: Cancer cachexia is a co-morbidity highly prevalent in pancreatic ductal adenocarcinoma (PDAC) patients and results in a decreased quality of life for this population. Cachexia is characterized by losses in muscle and adipose tissue mass, which are persistent and refractory to interventions, such as nutritional support. Under nutritional stress, the liver shifts metabolism to supply energy-rich molecules (ketone bodies, glucose) to fuel the brain and skeletal muscle. In this study we test the hypothesis that this adaptive response to undernutrition is impaired in PDAC cachexia, thereby exacerbating the systemic energy deficit and resulting in accelerated skeletal muscle wasting. Recent literature highlights the relationship between IL-6 signaling and PDAC cachexia. We hypothesize that in addition to acting directly on muscle and adipose tissue, IL-6 acts on the liver to drive metabolic changes associated with impaired adaptive response to undernutrition.

Materials/Methods: Adult mice received orthotopic injections of the PDAC cell line KrasG12D; p53R172H/+; Pdx1-cre (KPC) or PBS sham. In a series of 2x2 factorial studies, PDAC and sham mice were nutritionally challenged with chronic caloric restriction or acute fasting. Food intake and body composition were measured longitudinally. Blood glucose and ketones were measured at endpoint. Ketogenic potential was assessed using octanoate challenge after fasting. qPCR was used to assess hepatic metabolism and IL-6 signaling, and muscle atrophy. Circulating IL-6 was measured by ELISA. In vitro assays were completed using C2C12 myoblasts and conditioned media from KPC cells. Whole body IL-6 knock out mice and hepatocyte-specific STAT3 knock out mice were used to assess the dependency of liver metabolic changes on IL-6 signaling.

Results: PDAC mice maintained on caloric restriction were more susceptible to skeletal muscle loss than sham mice, even early in tumor development, when no wasting is observed in ad-lib fed mice. PDAC mice also display suppressed blood ketone and glucose mobilization. Octanoate challenge revealed impaired ketogenic potential in PDAC mice, which was associated with decreased expression of genes regulating beta oxidation and ketogenesis in the liver (Ppara, Acox1, Acadm, Hmgcs2, Ehhadh, Acaa2, Bdh1). In vitro measurements of myotube atrophy demonstrated that physiologic levels of ketone exposure protected myotubes from KPC conditioned media-induced atrophy. Genetic ablation of IL-6 or hepatic IL-6 signaling in PDAC mice ameliorated the metabolic changes in the liver and loss of skeletal muscle mass.

Conclusions: Our work identifies IL-6 as a regulator of hepatic metabolism and posits the liver as a central hub for mediating cancer cachexia. Restoration of hepatic ketone metabolism is a promising avenue for preventing muscle atrophy in PDAC-associated cachexia.

Citation Format: Paige C. Arneson-Wissink, Heike Mendez, Katherine Pelz, Jessica Dickie, Xinxia Zhu, Brennan Olson, Daniel L. Marks, Aaron J. Grossberg. Tumor-derived IL-6 impairs hepatic adaptive response to undernutrition in pancreatic cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2175.