Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma

SIMPLE SUMMARY: Synovial sarcoma (SS) is associated with a high risk of recurrence and poor prognosis, and no biomarker useful in monitoring tumor burden exists. We identified monocarboxylate transporter 1 (MCT1) expressed in extracellular vesicles (EVs) derived from synovial sarcoma as a potential such marker. Circulating levels of MCT1(+)CD9(+) EVs were significantly correlated with tumor volume in a SS mouse model. Serum levels of MCT1(+)CD9(+) EVs reflected tumor burden and treatment response in SS patients. Patients with MCT1 expression on the plasma membrane have significantly worse overall survival than those with nuclear expression. Silencing of MCT1 reduced the malignant phenotype including cellular viability, migration, and invasion of SS cells. MCT1 may thus be a promising novel target for liquid biopsies and a novel therapeutic target. ABSTRACT: The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1(+)CD9(+) EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume (p = 0.003). Furthermore, serum levels of MCT1(+)CD9(+) EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival (p = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1(+)CD9(+) EVs and indicates the therapeutic potential of MCT1 in SS.