Molecular Mechanisms of Muscle and Fat Wasting in Pancreatic Cancer Cachexia

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Cancer cachexia, or muscle wasting with chronic inflammation and dysmetabolism, causes roughly 1/3 of cancer deaths. Cachexia is most prevalent in pancreatic ductal adenocarcinoma (PDAC), afflicting >85% of patients. Loss of muscle mass in patients reduces performance status, predisposes to illness, including respiratory infections and heart failure, and reduces response to and tolerance of anti-cancer therapies. Moreover, presence of cachexia or low performance status due to wasting is a contraindication for aggressive treatment protocols and can trigger treatment withdrawal. Pre-clinical studies from our group and others prove that targeting circulating cachexia factors can preserve muscle, improve function and lengthen survival even without effects on tumor growth. Thus preventing muscle loss could promote quality and length of life and potential for cure. Considerable evidence implicates Interleukin-6 (IL-6) in PDAC and PDAC cachexia. IL-6 is well known to mediate both cachexia as well as PDAC progression and escape from immune surveillance. However, IL-6 is merely one of a family of related factors that all bind to GP130 to elicit common signaling and overlapping biological effects. Analyses of patients and mice demonstrate that adipose is lost first and preferentially in PDAC. Precedent in diabetes and other cancer models suggests that adipose is not a passive victim, but rather could be source of toxic metabolites that injure oxidative tissues like heart and muscle, ultimately causing their wasting. Thus, GP130 signaling combined with lipotoxicity could mediate heart and skeletal muscle wasting in PDAC. Hypothesis: IL-6 family cytokines are secreted by PDAC cells and also by the host in response to cancer. These cytokines elicit adipose lipolysis, cardiac and skeletal muscle wasting directly by signaling in those tissues through GP130. Cardiac and muscle wasting are also triggered indirectly when products of lipolysis accumulate in myocytes, enhancing cellular stress and metabolic dysfunction, leading to lipotoxicity and wasting. Blocking GP130 family cytokines should reduce wasting of fat, heart and skeletal muscle, promote response to therapy, and prolong life in PDAC. This project will leverage well-characterized pre-clinical models of pancreatic cancer, a PDAC cachexia biobank, and substantial experience in circulating mediators of cachexia to identify novel mediators, mechanisms and organ cross talk in PDAC cachexia. We will accomplish this in two Aims. AIM 1: Determine the contribution of tumor-derived and host-derived IL- 6 family/GP130 cytokines in clinically relevant mouse models and clinical specimens in PDAC cachexia. AIM 2. Determine the contribution of GP130 signaling in adipose tissue versus skeletal muscle in PDAC cachexia, using clinically relevant mouse models and patient samples.