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
  • 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: [email protected].
  • 9. Department of Clinical Nutrition, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: [email protected].
  • 10. Department of General Surgery, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China. Electronic address: [email protected].
  • 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: [email protected].
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.
Products