TWF2 Drives Tumor Progression and Sunitinib Resistance in Renal Cell Carcinoma through Hippo Signaling Suppression

  • Adv Sci (Weinh). 2025 Sep 15:e06367. doi: 10.1002/advs.202506367.
Liangmin Fu  1  2  3 ,  Wuyuan Liao  1  4 ,  Youyan Tan  2 ,  Hansen Lin  1 ,  Kun Ye  1 ,  Xinwei Zhou  1 ,  Mingjie Lin  1 ,  Kangbo Huang  5  6 ,  Minyu Chen  1 ,  Jietao Wei  2 ,  Haoqian Feng  1 ,  Yuhang Chen  1 ,  Jinwei Chen  1 ,  Bohong Guan  1 ,  Shan Li  7 ,  Zhengkun Zhang  1 ,  Anze Yu  1 ,  Zihao Feng  1 ,  Lizhen Zhang  1 ,  Guannan Shu  8 ,  Jun Lu  1 ,  Wei Chen  1 ,  Yihui Pan  9 ,  Jiefeng Yang  2 ,  Junhang Luo  1 ,  Li Luo  10
Affiliations
  • 1. Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 518880, China.
  • 2. Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 528406, China.
  • 3. Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China.
  • 4. Department of Urology, Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, Shenzhen, 518116, China.
  • 5. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 6. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
  • 7. Department of Urology, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
  • 8. Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, 510623, China.
  • 9. Department of Urology, the Third Affiliated Hospital of Soochow University, Changzhou, 213000, China.
  • 10. Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
PMID: 40948085 DOI: 10.1002/advs.202506367
Abstract

Renal cell carcinoma (RCC) remains a formidable clinical challenge, characterized by a high propensity for metastasis and the frequent emergence of intrinsic or acquired resistance to targeted therapies. However, the molecular mechanisms underlying sunitinib resistance and tumor progression in RCC are not fully understood. This study aims to identify Twinfilin actin-binding protein (TWF2) as a key mediator of tumor aggressiveness and therapeutic resistance. TWF2 expression is markedly upregulated in RCC cells, particularly in sunitinib-resistant subtypes, and significantly associated with poor prognosis and therapeutic nonresponsiveness. Functional analyses demonstrate that TWF2 promotes RCC cell invasion, migration, metastasis, and sunitinib resistance by inhibiting the Hippo signaling. Mechanistically, TWF2 interacts with Yes-associated protein (YAP) via the binding residues: TWF2 M99 and YAP M225. By competitively displacing large tumor suppressor kinase 1, TWF2 prevents YAP ubiquitination and degradation, leading to its stabilization and subsequent nuclear translocation. Mutation of the M99 residue abolishes the tumor-promoting activity of TWF2. Furthermore, salvianolic acid E is identified as a small-molecule inhibitor of the TWF2-YAP interaction, and synergistically enhances sunitinib efficacy in RCC cell lines and patient-derived xenograft models. These findings highlight TWF2 as a promising therapeutic target for overcoming drug resistance in RCC.

Keywords
Hippo signaling; TWF2; renal cell carcinoma; sunitinib resistance; tumor progression.
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