Muscle-tumor Metabolic Cross-talk Drives Inflammation And Metastasis

Metastasis significantly contributes to the dire outcomes in cancer, being responsible for the majority of cancer-related fatalities. While extensive research has been conducted on the intrinsic alterations within cancer cells that enable their spread throughout the body, the influence of the host's metabolism in this process remains poorly understood. Interestingly, heme, an iron-containing molecule, has been increasingly recognized for its role in cancer progression, being vital for cellular functions such as oxygen transport and inflammation. We previously described that skeletal muscle from tumor-bearing mice presents a significant increase in heme export, suggesting that the export into the bloodstream might potentially fuel tumor biology. To this aim, we examined the role of muscular heme in influencing the metastatic capabilities in a model of Lewis Lung Carcinoma, delving into the relationship between the export of heme from skeletal muscles and the progress of tumours into metastatic stages. A mouse model with a skeletal-muscle specific knockout of the heme exporter (FLVCR1a mKO) was created. This significantly lowered lung metastasis without affecting the primary tumor. Additionally, FLVCR1a mKO mice had lower neutrophil levels both in the blood and the primary tumor, highlighting a link between muscle-derived heme, neutrophil activity, and metastatic potential. Moreover, a higher coverage of tumor vessels was found in FLVCR1a mKO mice resulting in a lower migration of cancerous cell throughout the circulation. Altogether these features disfavour the primary tumor in colonizing other sites of the host, hence reduced metastasis. Further research is required to validate this model in other cancer types with the aim to design new therapies that can modulate heme dynamics in oncological patients improving their prognosis.