胰腺导管腺癌（PDAC）因其隐匿的发病和快速发展而成为临床难以克服的最常见的恶性肿瘤之一。为了进一步改善PDAC患者的预后，寻找新的诊断标志物和治疗靶点显得迫在眉睫。V-set和免疫球蛋白结构域含有2（VSIG2）属于免疫球蛋白超家族（IgSF），在调节肿瘤免疫逃逸过程中具有共抑制分子的功能。然而，VSIG2在PDAC中的作用及相关机制尚不清楚。通过生物信息学分析、免疫组织化学、实时定量PCR和蛋白质印迹等方法检测PDAC组织和细胞中VSIG2的不同表达情况。利用CCK-8、集落形成、Transwell和刮痕实验评估PDAC细胞的增殖、侵袭和迁移能力。通过质谱法、共免疫沉淀和免疫荧光等方法确定VSIG2与晚期内质网/溶酶体适配器、MAPK和MTOR激活剂2（LAMTOR2）以及力霉素的机械靶点（mTOR）之间的关系。利用免疫印迹对GO和KEGG富集分析进行进一步的通路验证。此外，还采用皮下异种移植瘤模型和临床样本分析来进一步阐明VSIG2对PDAC的致癌作用。结果显示，PDAC组织和细胞中VSIG2高表达。VSIG2的过表达可促进PDAC细胞的增殖、侵袭和迁移能力，而抑制VSIG2则产生相反效应。机制上，VSIG2可以同时结合LAMTOR2和mTOR，增强两者之间的相互作用，进而提高mTOR和下游关键分子的磷酸化修饰活化水平。临床上，VSIG2的上调与PDAC患者的晚期分期、总生存期和无病生存期呈正相关。我们的研究揭示了VSIG2在PDAC中的高表达，促进了肿瘤的增殖、侵袭和转移。在机制上，VSIG2作为一个支架同时招募LAMTOR2和mTOR，稳定它们之间的相互作用，从而增强LAMTOR2介导的mTOR磷酸化活化。总之，VSIG2可能成为未来PDAC诊断和预后监测的生物标志物，同时，靶向VSIG2对PDAC的管理有望成为一种新策略。视频摘要。视频摘要。©2023年BioMed Central Ltd.，Springer Nature的一部分。

Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies to overcome clinically due to its insidious onset as well as rapid progression. It is urgent to seek new diagnostic markers and therapeutic targets in order to furthest ameliorate the prognosis of patients with PDAC. V-set and immunoglobulin domain containing 2 (VSIG2) belongs to immunoglobulin superfamily (IgSF), which function as coinhibitory molecule to mediate immune evasion of tumors. Nevertheless, the role of VSIG2 in PDAC and related mechanism still keep unclear.Different expression of VSIG2 in PDAC tissues and cells were detected by bioinformatic analysis, immunohistochemistry, real-time quantitative PCR as well as western blotting. CCK-8, colony formation, Transwell assay, and scratch experiment were utilized to assess proliferation, invasion and migration properties of PDAC cells. The relationship of VSIG2 with late endosomal/lysosomal adaptor, MAPK and MTOR activator 2 (LAMTOR2) and mechanistic target of rapamycin (mTOR) was identified using mass spectrometry, co-immunoprecipitation and immunofluorescence. GO and KEGG enrichment analysis were performed for further pathway verification using western blotting. Additionally, subcutaneous xenograft tumor model and clinical samples analysis were implemented to further elucidate the oncogenic effect of VSIG2 on PDAC in vivo and clinically.VSIG2 was highly expressed in PDAC tissues and cells. Overexpression of VSIG2 facilitated the proliferation, invasion and migration abilities of PDAC cells, while VSIG2-inhibition exerted opposite effects. Mechanistically, VSIG2 could simultaneously bind to LAMTOR2 and mTOR, thereby enhancing interaction between two molecules, which resulted in elevated phosphorylation-modificatory activation of mTOR and downstream key molecules. Clinically, up-regulation of VSIG2 was positively associated with advanced stage, overall survival and disease-free survival of PDAC patients.Our study disclosed that VSIG2 was overexpressed in PDAC, which promoted the proliferation, invasion and metastasis. Mechanically, VSIG2 acted as a scaffold to recruit LAMTOR2 and mTOR simultaneously, stabilize the interaction between them, thus enhancing LAMTOR2-mediated mTOR phosphorylated activation. Collectively, VSIG2 could be exploited as a biomarker for diagnosis and prognosis monitor of PDAC in the future, meanwhile, targeting VSIG2 in PDAC management is expected to be a novel strategy. Video Abstract. Video Abstract.© 2023. BioMed Central Ltd., part of Springer Nature.