Project Funding Details

Skeletal muscle is commonly perceived as a tissue primarily dedicated to mechanical movement. However, emerging evidence challenges this notion. It is now known for example that physical activity exerts a beneficial effect on metastasis, suggesting a potential active involvement of skeletal muscle in cancer progression. We generated an FLVCR1a muscle-specific KO which is resistant to metastasis development. Supporting the concept that muscle function can be involved in cancer progression. By studying muscle transcriptome during tumor growth, we previously identified dysregulated expression of two secreted factors: erythroferrone (ERFE) the negative regulator of hepcidin and the iron sequestering protein lipocalin 2 (LCN2). Our preliminary data indicate that alteration of iron metabolism by FLVCR1a knock down in the skeletal muscle results in a decrease number of metastasis. Our working hypothesis posits that skeletal muscle plays a role in tumor progression through the secretion of specific myokines, which ultimately impact iron metabolism. Specifically, we hypothesize that muscle-secreted factors, particularly erythroferrone (ERFE) and lipocalin 2 (LCN2), can influence cancer progression by modulating iron metabolism. Furthermore, we suggest that ERFE may contribute to metastatic dissemination, while LCN2 may play a role in muscle wasting. Our objective is to define the molecular mechanisms by which previously identified myokines affect cancer progression and metastatic dissemination. In particular, we want to understand the impact of muscle FLVCR1a KD in metastasis promotion (WP1), characterize the role of LCN2 in cancer-related muscle wasting (WP2), address the role of ERFE both in cachexia and metastasis (WP3) and finally evaluate the impact of hepcidin during metastasis formation and cancer progression (WP4). We will utilize in vivo and in vitro models, including mouse knockout models, cell culture systems proteomic analyses and single cell RNA sequencing, to dissect the molecular mechanisms underlying the interaction between skeletal muscle and cancer cells. We expect to provide a formal proof that skeletal muscle influences cancer progression and particularly metastatic dissemination. This work, by uncovering novel insights into the interplay between skeletal muscle and cancer metastasis might help to identify potential novel therapeutic targets and early markers for metastatic dissemination. This project aims to shift the paradigm of skeletal muscle as a mere bystander in cancer progression to an active contributor. By elucidating the role of muscle-secreted factors, we aim to develop innovative strategies for fighting metastasis and mitigating muscle wasting in cancer patients.