Hana Yao

Background/Objectives: Synovial sarcoma (SS) is a malignant soft tissue neoplasm with good outcomes in adolescents with localized tumors, but poor outcomes in older adults and in advanced or metastatic cases. Targeting cancer metabolism, such as glutamine metabolism, is a promising therapeutic strategy. In this study, we investigated glutamine dependency in SS and assessed the therapeutic potential of inhibiting the glutamine transporter ASCT2 using V9302. Methods: Immunohistochemistry (IHC) was used to evaluate ASCT2 expression in SS and liposarcoma (LPS) specimen. The effects of glutamine deprivation and V9302 were examined in a SS cell line (HS-SY-II), patient-derived SS cells (SSH1), and a normal cell line (HEK293). Cell viability, apoptosis, and protein expression were assessed using the CCK-8 assay, flow cytometry, and Western blotting, respectively. The therapeutic efficacy of V9302 was evaluated in a xenograft model using IHC. Results: ASCT2 expression was elevated in SS tumor tissues compared with adjacent normal tissues and LPS specimens. Both the HS-SY-II cell line and SSH1 cells exhibited strong glutamine dependency for proliferation. V9302 selectively reduced HS-SY-II cell viability by suppressing the AKT/mTOR signaling pathway and inducing apoptosis via caspase-3 activation, with minimal effects on control cells. In vivo, V9302 administration significantly inhibited tumor growth without inducing systemic toxicity, and IHC of the treated tumors confirmed the suppression of the mTOR pathway and induction of apoptosis. Conclusions: Our findings suggest that SS is a glutamine-dependent malignancy and validate ASCT2 as a promising therapeutic target. The ASCT2 inhibitor V9302 demonstrated therapeutic efficacy both in vitro and in vivo, supporting its potential as a therapeutic agent for SS.

Wide resection is the main treatment for sarcomas; however, when they are located near major nerves, their sacrifices might affect limb function. The efficacy of ethanol adjuvant therapy for sarcomas has not been established. In this study, the anti-tumor effect of ethanol, as well as its neurotoxicity, were assessed. In vitro anti-tumor effect of ethanol as evaluated using MTT, wound healing, and invasion assays on a synovial sarcoma cell line (HS-SY-II). In vivo, an assessment was conducted in nude mice (implanted with subcutaneous HS-SY-II) treated with different ethanol concentrations after surgery with a close margin. Sciatic nerve neurotoxicity was assessed with electrophysiological and histological examination. In vitro, ethanol concentrations at 30% and higher showed cytotoxic effects in MTT assay and markedly reduced migration and invasive ability of HS-SY-II. In vivo, both 30% and 99.5% ethanol concentrations, compared to 0% concentration, significantly reduced the local recurrence. However, in the group treated with 99.5% ethanol, nerve conduction tests showed prolonged latency and decreased amplitude, and morphological changes suggestive of nerve degeneration were observed in the sciatic nerve, while the 30% ethanol did not cause neurological damage. In conclusion, 30% is the optimal concentration for ethanol adjuvant therapy after close-margin surgery for sarcoma.