获得性高水平脱模谷蛋白-2驱动的脱模小体组装增强了ER+乳腺癌的表型可塑性和内分泌抗性。

IF 9.1 1区 医学 Q1 ONCOLOGY
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引用次数: 0

摘要

内分泌治疗的获得性耐药性仍然是一项重大的临床挑战。在这项研究中,我们发现desmoglein-2(DSG2)在ER+乳腺癌(BC)的获得性内分泌耐药性和细胞可塑性中起着重要作用。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抑制会导致癌细胞群中DSG2的特异性增加,这反过来又会增强体外和体内脱落小体的形成以及细胞表型的可塑性,从而促进对治疗的耐药性。在氟维司群耐药的异种移植模型中,DSG2的耗竭可减少肿瘤发生和转移,并提高氟维司群的效率。从机理上讲,DSG2与JUP和Vimentin形成脱粘体复合物,并触发Wnt/PCP信号。我们的研究表明,DSG2水平的升高、ER水平的降低和Wnt/PCP通路的激活预示着患者的生存率较低,这表明可以利用DSG2高的特征进行治疗干预。我们的分析强调了抗雌激素治疗后DSG2介导的脱雌作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer

Enhanced desmosome assembly driven by acquired high-level desmoglein-2 promotes phenotypic plasticity and endocrine resistance in ER+ breast cancer

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.

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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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