Investigating the role of muscle-derived lipocalin-2 and iron in cancer cachexia and tumor growth (Fellowships for Italy Post-Doc 2023)

Background Cancer cachexia is a devastating syndrome that results in muscle wasting and weakness, decreased quality of life, and poor clinical outcomes. The mechanisms underlying this condition are poorly understood, but recently, we identified dysregulation of iron metabolism as a potential contributor. Hypothesis The goal of this project is to investigate the signaling axis that disrupts iron metabolism in cachexia and its implication for cancer progression. We hypothesize that the overexpression of Lipocalin-2, an iron sequestering protein, in the skeletal muscle depletes mitochondrial iron homeostasis, leading to skeletal muscle atrophy in cancer. Furthermore we believe that the secretion of Lipocalin2 from the skeletal muscle might foster cancer progression. Aims We aim to : 1) Confirm the involvement of Lipocalin-2 and mitochondrial iron depletion in the atrophic process induced by cancer in skeletal muscle and 2) evaluate the impact of muscle-derived Lipocalin-2 on cancer progression. Experimental Design The experimental design involves using a recombinant AAV9 vector to specifically silence Lipocalin-2 in muscle tissue and assessing its impact on skeletal muscle atrophy, as well as on tumor growth in a mouse model of cancer cachexia. Additionally, in vitro assays will be conducted to characterize the molecular mechanism by which Lipocalin-2 induces atrophy in C2C12 myotubes, but also to evaluate the effects of Lipocalin-2 on cancer cells. Expected Results With this project, we expect to shed light on the role played by muscle-derived Lipocalin-2 in cancer progression. Specifically, we aim to validate the role of Lipocalin-2 as an iron-related mediator of skeletal muscle atrophy in cancer cachexia. Furthermore we will get valuable insights into the crosstalk between tumor and muscle. Impact On Cancer The findings from this project have the potential to provide a better understanding of the mechanisms underlying cancer cachexia and may identify muscle-derived lipocalin-2 as a new therapeutic target for this debilitating condition. Moreover, investigating the impact of muscle-derived LCN2 on cancer progression may shed light on the role of this protein in cancer and provide insights into potential targets for cancer treatment.