pERK transition-induced directional mode switching promotes epithelial tumor cell migration

• 成果类型: Article
• 署名作者: Yu, Huijing; Xiao, Guanli; Gu, Mingyao; Zhang, Liting; Xia, Ming; Mo, Shimin; Zhao, Yuying; Wei, Chaoliang
• 署名单位: Shenzhen University; Shenzhen University; Shenzhen Longhua District Central Hospital; Guangzhou Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14353
• DOI: 10.1073/pnas.2318871121
• 发表日期: 2024-12-17
• 关键词: erk inhibitor; activation; DISCOVERY; paxillin; braf; fak

摘要

Increasing evidence suggests that tumor cells exhibit extreme plasticity in migration modes in order to adapt to microenvironments. However, the underlying mechanism for governing the migration mode switching is still unclear. Here, we revealed that epithelial tumor cells could develop a stable directional mode driven by hyperactivated ERK activity. This highly activated and dynamically changing ERK activity, called pERK transition, is crucial for inducing the switch from pauses state to directional movement and is also necessary for maintaining epithelial tumor cells in the directional mode. PERK transition integrated pERK surf, the dynamic and localized ERK activity at the leading edge. The sequential activation of RhoA and Rac1 by pERK transition played critical roles in generation of pERK surf activity through a movement feedback mechanism. PERK transition activity converted the orderly collective migration into the disordered dispersal movement, enhanced the invasiveness of epithelial tumor cells, and promoted their metastasis in immune- deficient mice. These findings revealed that invasion of tumor cells and provide evidence for the mechanism underlying migration mode switching in epithelial tumor cells.