1. Academic Validation
  2. Targeting FOXM1 condensates reduces breast tumour growth and metastasis

Targeting FOXM1 condensates reduces breast tumour growth and metastasis

  • Nature. 2025 Jan 15. doi: 10.1038/s41586-024-08421-w.
Feng Xie # 1 2 Xiaoxue Zhou # 3 Yu Ran 4 Ran Li 3 Jing Zou 4 Shiyun Wan 5 Peng Su 6 Xuli Meng 6 Haiyan Yan 3 Huasong Lu 4 Heng Ru 4 Hai Hu 7 Zhengwei Mao 8 Bing Yang 9 Fangfang Zhou 10 Long Zhang 11 12 13
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China. xiefeng@suda.edu.cn.
  • 2 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China. xiefeng@suda.edu.cn.
  • 3 School of Medicine, Hangzhou City University, Hangzhou, China.
  • 4 Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 5 The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
  • 6 Key Laboratory for Diagnosis and Treatment of Upper Limb Edema and Stasis of Breast Cancer, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Hangzhou, China.
  • 7 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
  • 8 MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. zwmao@zju.edu.cn.
  • 9 Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. bingyang@zju.edu.cn.
  • 10 The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China. zhoufangfang@suda.edu.cn.
  • 11 Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, China. l_zhang@zju.edu.cn.
  • 12 Life Sciences Institute and State Key Laboratory of Transvascular Implantation Devices of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. l_zhang@zju.edu.cn.
  • 13 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. l_zhang@zju.edu.cn.
  • # Contributed equally.
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.

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