A VEGFA-mediated crosstalk between macrophages and adipocytes drives lung cancer-associated adipose wasting

Lung cancer is the leading cause of cancer-related mortality on a global scale. Cancer-associated cachexia (CAC) affects more than 20% of patients diagnosed with lung cancer and is a major contributor to mortality among these individuals. Analysis of publicly available proteomics data revealed that patients affected by lung CAC exhibited elevated levels of vascular endothelial growth factor A (VEGFA) in their serum. This increase in VEGFA levels was particularly heightened in patients with more than 20% visceral adipose tissue waste. Despite a high number of studies aimed at clarifying the correlation between inflammatory cytokines and CAC, as well as cancer progression, a lack of understanding about the origin of adipose wasting persists. Furthermore, individuals who developed CAC exhibited an enrichment in the recruitment and activation of myeloid cells, suggesting the involvement of macrophages. Macrophages represent one of the most abundant immune cell types in the tumour microenvironment (TME). Numerous evidence highlights this population as a major contributor to adipose tissue dynamics, particularly in terms of adipose loss. Recent studies have demonstrated that macrophages have the capacity to secrete proangiogenic factors belonging to the vascular endothelial growth factor (VEGF) family, including VEGFA. This finding is supported by the results of single-cell RNAseq data analysis we conducted on patients diagnosed with lung cancer. In addition, our original transcriptomics data of adipose tissue derived from mice injected with Lewis lung carcinoma cells show that adipose tissue in animal models of CAC at different time points show high levels of VEGF receptor 1: its expression increases with a worsening of the disease. In particular, it was observed that adipose tissue from mice exhibiting a more severe cachectic phenotype demonstrated a diminished capacity in lipid biosynthesis, a suppressed process of fat cell differentiation, and elevated levels of lipolysis. These findings indicate a potential association between the secretion of VEGFA by macrophages and the regulation of lipid metabolism. Therefore, we hypothesise a potential mechanism of crosstalk between macrophages and adipocytes that could become a novel therapeutic target to block adipose tissue wasting, improving cancer prognosis.