对内分泌治疗的获得性耐药仍然是一个重大的临床挑战。在这项研究中，我们发现桥粒芯糖蛋白-2 (DSG2) 在 ER 乳腺癌 (BC) 的获得性内分泌抵抗和细胞可塑性中发挥着重要作用。通过使用单细胞 RNA-seq 分析成熟的氟维司群耐药 ER BC 模型，我们发现 ER 抑制导致癌细胞群中 DSG2 的特异性增加，进而增强体外和体内桥粒的形成以及细胞促进治疗抵抗的表型可塑性。 DSG2 耗竭减少了氟维司群耐药异种移植模型中的肿瘤发生和转移，并提高了氟维司群效率。从机制上讲，DSG2 与 JUP 和 Vimentin 形成桥粒复合物并触发 Wnt/PCP 信号传导。我们发现，DSG2 水平升高、ER 水平降低和 Wnt/PCP 通路激活可预测生存率较差，这表明 DSG2high 特征可用于治疗干预。我们的分析强调了抗雌激素治疗后 DSG2 介导的桥粒连接的关键作用。版权所有 © 2024。由 Elsevier B.V. 出版。

Acquired resistance to endocrine treatments remains a major clinical challenge. In this study, we found that desmoglein-2 (DSG2) plays a major role in acquired endocrine resistance and cellular plasticity in ER+ breast cancer (BC). By analysing the well-established fulvestrant-resistant ER+ BC model using single-cell RNA-seq, we revealed that ER inhibition leads to a specific increase in DSG2 in cancer cell populations, which in turn enhances desmosome formation in vitro and in vivo and cell phenotypic plasticity that promotes resistance to treatment. DSG2 depletion reduced tumorigenesis and metastasis in fulvestrant-resistant xenograft models and promoted fulvestrant efficiency. Mechanistically, DSG2 forms a desmosome complex with JUP and Vimentin and triggers Wnt/PCP signalling. We showed that elevated DSG2 levels, along with reduced ER levels and an activated Wnt/PCP pathway, predicted poor survival, suggesting that a DSG2high signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.Copyright © 2024. Published by Elsevier B.V.