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.
背景/目的：滑膜肉瘤是一种恶性软组织肿瘤，在患有局限性肿瘤的青少年中预后良好，但在老年患者以及晚期或转移性病例中预后较差。靶向癌症代谢，如谷氨酰胺代谢，是一种有前景的治疗策略。本研究探讨了滑膜肉瘤对谷氨酰胺的依赖性，并评估了使用V9302抑制谷氨酰胺转运蛋白ASCT2的治疗潜力。 方法：采用免疫组织化学法评估滑膜肉瘤和脂肪肉瘤标本中ASCT2的表达。在滑膜肉瘤细胞系（HS-SY-II）、患者来源的滑膜肉瘤细胞（SSH1）和正常细胞系（HEK293）中检测谷氨酰胺剥夺和V9302的作用。分别使用CCK-8法、流式细胞术和蛋白质印迹法评估细胞活力、凋亡和蛋白表达。通过免疫组织化学在异种移植模型中评估V9302的治疗效果。 结果：与邻近正常组织和脂肪肉瘤标本相比，滑膜肉瘤肿瘤组织中ASCT2表达升高。HS-SY-II细胞系和SSH1细胞均表现出强烈的谷氨酰胺依赖性以维持增殖。V9302通过抑制AKT/mTOR信号通路和激活caspase-3诱导凋亡，选择性降低HS-SY-II细胞活力，而对对照细胞影响甚微。在体内，给予V9302显著抑制肿瘤生长且未引起全身毒性，治疗肿瘤的免疫组化结果证实了mTOR通路的抑制和凋亡的诱导。 结论：我们的研究结果表明滑膜肉瘤是一种谷氨酰胺依赖性恶性肿瘤，并证实ASCT2是一个有前景的治疗靶点。ASCT2抑制剂V9302在体外和体内均显示出治疗效果，支持其作为滑膜肉瘤治疗药物的潜力。
Targeting Glutamine Transporters as a Novel Drug Therapy for Synovial Sarcoma
肿瘤(癌症)患者之家