Department of Clinical Laboratory, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Laboratory Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cancer Lett. 2024 Sep 28;600:217179. doi: 10.1016/j.canlet.2024.217179. Epub 2024 Aug 21.
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 DSG2 signature could be exploited for therapeutic interventions. Our analysis highlighted the critical role of DSG2-mediated desmosomal junctions following antiestrogen treatment.
获得性内分泌治疗耐药仍是临床上的一个重大挑战。在这项研究中，我们发现桥粒蛋白-2（DSG2）在 ER 阳性乳腺癌（BC）的获得性内分泌耐药和细胞可塑性中起着重要作用。通过对已建立的氟维司群耐药 ER 阳性 BC 模型进行单细胞 RNA 测序分析，我们揭示了 ER 抑制导致癌细胞群体中 DSG2 的特异性增加，进而增强体外和体内的桥粒形成以及促进治疗耐药的细胞表型可塑性。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，并提高了氟维司群的疗效。在机制上，DSG2 与 JUP 和 Vimentin 形成桥粒复合物，并触发 Wnt/PCP 信号通路。我们表明，DSG2 水平升高，同时 ER 水平降低和 Wnt/PCP 通路激活，预示着预后不良，提示 DSG2 标志物可用于治疗干预。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。
