Tumor-borne mediators trigger heart atrophy and alter cardiac metabolism in cancer cachexia

Abstract

Cancer cachexia affects the majority of patients suffering from advanced cancers, thereby reducing response to cancer treatment, quality of life and survival. Despite the tremendous research in the cancer cachexia field, the etiology remains elusive and cachexia still represents an unmet medical need as preventive or therapeutic approaches are lacking. While skeletal muscle and adipose tissue have been studied extensively in this context, the impact of cancer cachexia on other peripheral organs remains mostly unknown. Therefore, the present study investigated the impact of cancer-related cachexia on the cardiac muscle and the role of tumor-secreted factors in this context. By using the cachectic Colon-26 (C26) allograft and the adenomatous polyposis coli (APC) mouse model for colorectal cancer it was shown that cardiac performance was impaired in the course of cachexia. This was associated with reduced expression of genes encoding for contractile proteins, but not an increase in fibrosis. In addition, cachectic mice developed atrophy resulting from a reduction in cardiomyocyte size which was primarily mediated through autophagy. In contrast to previous studies in skeletal muscle, activation of the ubiquitin-proteasome system was not detected. Additionally, the non-cachectic mouse colon 38 (MC38) allograft model did not show any alterations in heart function, size or gene expression. To identify cell-specific molecular changes in cardiomyocytes, an in vitro model was established where primary cardiomyocytes were exposed to conditioned medium from cachexia- or non-cachexia-inducing cells. Similar to the observations in cachectic animals, primary cardiomyocytes treated with conditioned medium from C26 cells developed atrophy. Gene expression analysis of hearts from the C26-bearing mice and of primary mouse cardiomyocytes treated with C26-conditioned medium revealed that cardiac fatty acid (FA) metabolism was altered under cachectic conditions. Transcription levels of genes encoding for proteins involved in FA transport and mitochondrial -oxidation were elevated, whereas expression of genes encoding for glucose transporters were reduced. Further analysis showed that triglyceride storage in both hearts and primary cardiomyocytes was diminished, and functional analysis by metabolic flux analysis revealed that palmitate-driven -oxidation and uncoupling capacity were increased under cachectic conditions. The results obtained from the established in vitro model suggested that the cachexia-induced effects on the heart were mediated by tumor-secreted factors in a cell autonomous manner. Therefore, an unbiased differential secretome analysis of C26 cells combined with high-throughput cardiomyocyte phenotyping was performed to define a set of tumor-secreted mediators with cachexia-inducing capacities. A signature of seven “cachexokines” was sufficient to mediate atrophy and aberrant FA metabolism in primary cardiomyocytes. The most promising candidate amongst these seven was Ataxin10 which showed elevated serum levels in cachectic mice. Taken together, this study demonstrates that cardiac dysfunction is an understudied clinical feature of cancer cachexia and that alterations in FA metabolism represent a distinct feature of the cachectic heart. In addition, this study provides an unbiased and functional screening setup for the investigation of tumor-secreted factors with cachexia-inducing capacity and delivers a new therapeutic starting point.