浙江大学张龙等近期取得重要工作进展。他们研究提出，靶向FOXM1凝聚物可抑制乳腺肿瘤生长与转移。相关研究成果2025年1月15日在线发表于《自然》杂志上。

据介绍，鉴定相分离结构仍然颇具挑战，且目前缺乏有效的干预方法 。

研究人员对乳腺肿瘤细胞中的相分离蛋白进行了筛选，并确定FOXM1为最佳的候选蛋白。致癌性的FOXM1与FKH共有DNA元件发生液-液相分离（LLPS），并在细胞核内对转录装置进行区室化，从而维持对肿瘤转移生长至关重要的染色质可及性和超级增强子结构。

通过筛选表观遗传学化合物文库，研究人员发现，AMPK激动剂可抑制FOXM1凝聚。AMPK在FOXM1的内在无序区域（IDR）使其磷酸化，破坏凝聚物，减少致癌转录，积累双链DNA以刺激先天免疫反应，并赋予离散的FOXM1激活免疫原性相关基因表达的能力。

通过开发遗传密码扩展正交系统，研究人员证明特定IDR1位点的磷酸基团会引起静电排斥，从而消除FOXM1的液-液相分离和聚集。研究人员设计了一种靶向IDR1并携带AMPK磷酸化残基的肽，以破坏FOXM1的液-液相分离，结果显示该肽可抑制肿瘤恶性程度、挽救肿瘤免疫原性并改善肿瘤免疫治疗效果。

总之，这一研究为FOXM1的功能和机制提供了全新且深入的见解，并开发出在临床上具有广阔应用前景的方法。

附：英文原文

Title: Targeting FOXM1 condensates reduces breast tumour growth and metastasis

Author: Xie, Feng, Zhou, Xiaoxue, Ran, Yu, Li, Ran, Zou, Jing, Wan, Shiyun, Su, Peng, Meng, Xuli, Yan, Haiyan, Lu, Huasong, Ru, Heng, Hu, Hai, Mao, Zhengwei, Yang, Bing, Zhou, Fangfang, Zhang, Long

Issue&Volume: 2025-01-15

Abstract: Identifying phase-separated structures remains challenging, and effective intervention methods are currently lacking1. Here we screened for phase-separated proteins in breast tumour cells and identified forkhead (FKH) box protein M1 (FOXM1) as the most prominent candidate. Oncogenic FOXM1 underwent liquid–liquid phase separation (LLPS) with FKH consensus DNA element, and compartmentalized the transcription apparatus in the nucleus, thereby sustaining chromatin accessibility and super-enhancer landscapes crucial for tumour metastatic outgrowth. Screening an epigenetics compound library identified AMPK agonists as suppressors of FOXM1 condensation. AMPK phosphorylated FOXM1 in the intrinsically disordered region (IDR), perturbing condensates, reducing oncogenic transcription, accumulating double-stranded DNA to stimulate innate immune responses, and endowing discrete FOXM1 with the ability to activate immunogenicity-related gene expressions. By developing a genetic code-expansion orthogonal system, we demonstrated that a phosphoryl moiety at a specific IDR1 site causes electrostatic repulsion, thereby abolishing FOXM1 LLPS and aggregation. A peptide targeting IDR1 and carrying the AMPK-phosphorylated residue was designed to disrupt FOXM1 LLPS and was shown to inhibit tumour malignancy, rescue tumour immunogenicity and improve tumour immunotherapy. Together, these findings provide novel and in-depth insights on function and mechanism of FOXM1 and develop methodologies that hold promising implications in clinics.

DOI: 10.1038/s41586-024-08421-w

Source:https://www.nature.com/articles/s41586-024-08421-w