2. Academic Validation
  3. Disrupting Lipid Raft Microdomains to Block Polyploid Giant Cancer Cell Budding and Enhance Radiotherapy Response

Disrupting Lipid Raft Microdomains to Block Polyploid Giant Cancer Cell Budding and Enhance Radiotherapy Response

  • Adv Sci (Weinh). 2025 Dec 2:e19698. doi: 10.1002/advs.202519698.
Zheng Deng 1 2 3,  Haoran Sun 1 2,  Jin Cheng 1 2,  Ruyi Zhao 4,  Jianzhu Xie 1 2,  Yanwei Song 1 2,  Yucui Zhao 1 2,  Chenwei Lin 3,  Binjie Hu 1 2,  Yanping Gong 1 2,  Jun Lin 5,  Sijia He 1 2,  Yuntao Luo 6,  Minghui Zhao 1 2,  Yiwei Wang 1 2,  Ming Jiao 7,  Yuqin Yang 7,  Jikun Li 8,  Shujie Xia 3,  Chuanyuan Li 9,  Qian Huang 1 2
Affiliations

Affiliations

  • 1 Cancer Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 2 Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 3 Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 4 Department of Vascular Surgery, Shanghai General Hospital of Nanjing Medical University, Shanghai, 201620, China.
  • 5 Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 6 Clinical Microbiology Laboratory, Shanghai Center for Clinical Laboratory, Shanghai, 200126, China.
  • 7 Department of Laboratory Animal Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 8 Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 9 Institute for Molecular and Cellular Therapy, Chinese Institutes for Medical Research and School of Basic Medicine, Capital Medical University, Beijing, 100069, China.
PMID: 41330885 DOI: 10.1002/advs.202519698
Abstract

Radiotherapy failure often arises from tumor repopulation by treatment-resistant Cancer cells. Following irradiation, Cancer cells can undergo endoreplication to form polyploid giant Cancer cells (PGCCs)-radiation-persistent cells capable of generating progeny through a virus-like asymmetric budding process. While such membrane budding is evolutionarily conserved across archaea, viruses, and eukaryotic cells, its molecular mechanism in Cancer remains poorly defined. Here, a radiation-induced SNCG-FLOT2-CHMP4B signaling axis is identified as a key regulator of PGCC budding. Mechanistically, ASAH1 and SMPD2 maintain sphingolipid metabolic balance, while FLOT2 drives germination at lipid raft-enriched membrane microdomains, followed by CHMP4B-dependent abscission to release daughter cells. Disrupting these lipid raft structures-via statins or anti-PCSK9 antibodies-impairs budding, suppresses PGCC-derived tumor repopulation, and enhances radiosensitivity in vitro and in vivo. This findings uncover a conserved membrane remodeling program underlying PGCC budding and establish lipid raft disruption as a promising therapeutic approach to prevent tumor recurrence after radiotherapy. Clinically available lipid-lowering agents may thus serve as innovative radiosensitizers to improve radiotherapy outcomes.

Keywords

Budding; Polyploid giant cancer cells; Radiotherapy; Radio‐sensitization; Tumor repopulation.

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