2. Academic Validation
  3. Oncogenic GOPC-ROS1 fusion promotes the formation of lymphatic malformations by impairing tight junction and its crizotinib resistance through repressing ferroptosis

Oncogenic GOPC-ROS1 fusion promotes the formation of lymphatic malformations by impairing tight junction and its crizotinib resistance through repressing ferroptosis

  • Biochem Pharmacol. 2025 Aug 15;242(Pt 1):117243. doi: 10.1016/j.bcp.2025.117243.
Ruicheng Tian 1,  Zihan Weng 2,  Huisheng Liang 3,  Chengchen Zhang 4,  Qiao He 5,  Jing Li 6,  Rui Zhang 6,  Xiaowan Yin 7,  Dan Deng 8,  Li Hong 9,  Song Gu 10,  Zhiyan Zhan 11
Affiliations

Affiliations

  • 1 Department of Dermatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 2 Department of Information, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 3 Department of Gynecology, Zhongshan Hospital, Fudan University (Xiamen Branch), Xiamen, China.
  • 4 Clinical Research Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 5 Department of Pathology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 6 Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 7 National Clinical Research Center for Laboratory Medicine, Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang 110001, China.
  • 8 Department of Dermatology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: dengdan1234567@126.com.
  • 9 Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: hongli@scmc.com.cn.
  • 10 Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: gusong@shsmu.edu.cn.
  • 11 Clinical Research Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: zhanzhiyan@sjtu.edu.cn.
PMID: 40819798 DOI: 10.1016/j.bcp.2025.117243
Abstract

The complicacy of genetic abnormalities in lymphatic malformations (LMs) limits their treatment in clinical practice. In this study, we identified a complex LM with Golgi-associated PDZ and coiled-coil motif containing (GOPC)-proto-oncogene ROS 1 (ROS1) fusion that responds to crizotinib. The oncogenic roles of GOPC-ROS1 fusion in the formation of LMs remain unknown. This study showed that GOPC-ROS1 fusion promotes the proliferation, migration, and invasion of human lymphatic endothelial cells (HLECs). Moreover, fusion of GOPC and ROS1 enhances the catalytic activity of the ROS1 fragment as a receptor tyrosine kinase and alters the profiling of tyrosine phosphorylation in HLECs. Multiple novel tyrosine sites phosphorylated by GOPC-ROS1 in HLECs were validated. Impaired phosphorylation of ZO-1 protein at tyrosine 895, resulting from decreased co-location of GOPC-ROS1 and ZO-1 proteins, inhibits the tight junction of HLECs, which is important for the formation of functional lymphatic vessels. We next investigated the potential mechanisms of crizotinib resistance in GOPC-ROS1+ CLM. It was found that high glycolysis and low Ferroptosis levels, which are dependent on ENO1-phosY44, contribute to the crizotinib resistance of GOPC-ROS1+ HLECs. Targeting Ferroptosis by inhibiting System Xc- using sulfasalazine (SASP) represses the crizotinib resistance of GOPC-ROS1+ HLECs. A combination of SASP and crizotinib may be a potential therapeutic strategy for various GOPC-ROS1+ tumours.

Keywords

Crizotinib resistance; Ferroptosis; GOPC-ROS1 fusion; Lymphatic malformations; Tyrosine phosphorylation.

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