Heterologous Wingless Signaling Between Metastatic Cancer Xenograft and Host Tissues Induces Cachexia in Zebrafish Larvae

Extensive muscle loss is an irreversible affliction of both cancer patients (cachexia), and aging individuals (sarcopenia). In this study, we have exploited vertebrate zebrafish and the optical transparency of its larvae to address the underlying similarities between the two conditions, and the cause-and-effect relationships driving muscle loss. We found that zebrafish larvae microinjected with metastatic lung cancer cells exhibit cachectic phenotypes, mimicking the human pathology. Using bioinformatics, we found that the cancer cells, marked by active Wnt signaling, release the Secreted Frizzled-Related Protein 2 (SFRP2). Consistent with this, Wnt pathway target genes were found to be differentially expressed in cachectic larvae, perhaps through overactivation of its contemporaneously expressed zebrafish muscle-specific receptors. This causes structural alterations in mitochondria and the loss of myofibrillar pattern, resulting in impaired locomotion and cardiac tamponade, and, ultimately, muscle atrophy through apoptosis and necrosis. This work added to the understanding of the role of Wnt signaling in cachexia, and highlights the versatility of the zebrafish larval model. Further, it paved the way for developing therapeutic targets to manage muscle mass loss in elderly and diseased individuals.