Identification of tumor-borne mediators of pancreatic cancer-associated cachexia
Cancer cachexia describes a multi-factorial disease condition characterized by progressive loss of adipose tissue and skeletal muscle mass. Cachexia is particularly frequent in pancreatic ductal adenocarcinoma (PDAC) and is associated with decreased quality of life, more progressive disease, increased toxicity of cancer treatment and reduced survival. Despite its clinical importance, effective and routine therapeutic measures to counteract wasting are still lacking. Although the significance of cachectic metabolism as a response to tumor and/or host-derived mediators is increasingly recognized, the etiology of cancer cachexia at the molecular level is poorly understood.
We aim to identify and functionally characterize tumor-borne mediators ("cachexokines") of PDAC-associated cachexia. Based on amino acid labeling and mass-spectrometry, we defined a signature of proteins differentially secreted between cachexia-inducing and non-inducing carcinoma cells. By functional in vitro assays, we defined a subset of secreted factors contributing to muscle fiber atrophy and induced adipocyte lipolysis, representing central components cancer-induced wasting. Importantly, these “cachexokines” were also strongly secreted from murine and human pancreatic cancer cell lines as well as markedly increased in serum samples form cachectic pancreatic tumor-bearing mice. Strikingly, in a pilot cohort study, we found significantly elevated cachexokine levels in serum samples from PDAC patients characterized by body weight loss as compared to weight-stable patient samples.
By using in vitro and murine in vivo models, we aim to functionally characterize the identified cachexokines in order to elucidate specific molecular mechanisms of muscle and adipose tissue wasting as well as systemic catabolism. In addition, we will analyze the secretome from PDAC cell lines to define their relevance across cancer entities as well as potentially reveal additional PDAC-specific cachexia mediators. Finally, we will assess the predictive and diagnostic value of selected cachexokines in serum samples from PDAC patients and test their potential to serve as novel intervention points in combinatorial cancer/anti-cachexia therapy.
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