MUC1/CA15-3 identifies a clear cell renal carcinoma characterized by Sunitinib response with a specific metabolic signature

: Clear cell renal carcinoma (ccRCC) is a prevalent kidney cancer with limited effective biomarkers for prognosis and treatment guidance. Despite advancements, a significant portion of ccRCC cases progress to advanced stages, necessitating novel diagnostic tools. Here, we investigated the expression of MUC1 and its soluble form, CA15-3, in ccRCC, evaluating their potential as biomarkers for angiogenesis and response to sunitinib therapy. Molecular analyses showed that MUC1 expression was associated with angiogenesis, epithelial-mesenchymal transition, hypoxia/metabolism regulation, and complement system activation. In particular MUC1 overexpression correlated with increased microvascular density in vitro and in vivo models. Elevated CA15-3 levels were associated with tumor burden and predict clinical response to sunitinib in metastatic ccRCC. Metabolomic analysis showed that sunitinib-responding tumors were characterized by specific metabolic changes involving glucose and lipid metabolism, in association with impaired oxidative phosphorylation. MUC1 expressing ccRCC is a high angiogenic tumor that presents characteristics of increased aggressiveness, and a specific metabolic profile. Serum CA15-3 is a marker of poor survival and predicts response of sunitinib in patients with metastatic disease.