Metastasis contributes to the vast majority of cancer-related mortalities. Metastatic tumors secrete factors that systemically affect various organs leading to dysfunction and accelerated death. More than 80% of metastatic cancer patients experience a progressive and debilitating loss of muscle mass and function by a process known as cachexia. Cachectic patients suffer deterioration of diaphragm and cardiac muscles and often die prematurely due to respiratory and cardiac failure. The prognosis for these patients is further diminished by the fact that they are often too weak to tolerate standard doses of anti-cancer treatments. Cachexia is therefore an important determinant of therapeutic response, outcome and patient survival in advanced cancer patients. Although systemic metabolic derangements and chronic inflammation predominate in cachexia, the underlying molecular mechanisms driving its development are not well understood. Therefore, insights into the specific interventions that could either reverse or prevent cachexia are expected to improve treatment outcome, survival and quality of life in cancer patients. In this study, we identified a metal ion transporter, ZIP14 that was upregulated in cachectic muscles from five independent metastatic models, as well as in metastatic cancer patients. We find that TNF-alpha and TGF-beta cytokines upregulate ZIP14 in muscles, which in turn results in the accumulation of intracellular zinc. Increased zinc influx in muscle cells is associated with the degradation of myofibrillar proteins that contributes to muscle atrophy and muscle mass loss. Importantly, germline ablation or muscle-specific depletion of Zip14 markedly inhibits cancer-induced muscle wasting. Our study demonstrates a novel function of ZIP14 in muscles as a mediator of cachexia in advanced cancers. Insights from this study can be used to develop therapeutic strategies to prevent cachexia, and improve the survival and quality of life in metastatic cancer patients.

Citation Format: Anup Biswas, Gang Wang, Wanchao Ma, Courtney Coker, Kurenai Tanji, Manoj Kandpal, Ramana Davuluri, Swarnali Acharyya. Zinc transporter, ZIP14, as a mediator of systemic muscle wasting in metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5732.