Gallbladder carcinoma (GBC) exhibits poor prognosis due to local recurrence, metastasis, and resistance to targeted therapies. Using clinicopathological analyses of GBC patients along with molecular in vitro and tumor in vivo analysis of GBC cells, we showed that reduction of Dsg2 expression was highly associated with higher T stage, more perineural, and lymphatic invasion. Dsg2-depleted GBC cells exhibited significantly enhanced proliferation, migration, and invasiveness in vitro and tumor growth and metastasis in vivo through Src-mediated signaling activation. Interestingly, Dsg2 binding inhibited Src activation, whereas its loss activated cSrc-mediated EGFR plasma membrane clearance and cytoplasmic localization, which was associated with acquired EGFR-targeted therapy resistance and decreased overall survival. Inhibition of Src activity by dasatinib enhanced therapeutic response to anti-EGFR therapy. Dsg2 status can help stratify predicted patient response to anti-EGFR therapy and Src inhibition could be a promising strategy to improve the clinical efficacy of EGFR-targeted therapy.

胆囊癌（GBC）由于局部复发、转移和对靶向治疗的抵抗而表现出较差的预后。使用 GBC 患者的临床病理学分析以及 GBC 细胞的体外分子和肿瘤体内分析，我们发现 Dsg2 表达的降低与较高的 T 分期、更多的神经周围和淋巴浸润高度相关。Dsg2 耗尽的 GBC 细胞通过 Src 介导的信号激活在体外表现出显着增强的增殖、迁移和侵袭性以及在体内的肿瘤生长和转移。有趣的是，Dsg2 结合抑制了 Src 的激活，而它的缺失激活了 cSrc 介导的 EGFR 质膜清除和细胞质定位，这与获得性 EGFR 靶向治疗耐药性和总体存活率降低有关。达沙替尼对 Src 活性的抑制增强了对抗 EGFR 治疗的治疗反应。Dsg2 状态可以帮助对预测的患者对抗 EGFR 治疗的反应进行分层，而 Src 抑制可能是提高 EGFR 靶向治疗临床疗效的有希望的策略。