The PLEKHA1-TACC2 fusion gene drives tumorigenesis via vascular mimicry formation in esophageal squamous-cell carcinoma

  • Cell Death Differ. 2025 Jul 5. doi: 10.1038/s41418-025-01536-1.
Ting Yang  #  1 ,  Zhi-Rui Lin  #  2 ,  Tian-Liang Xia  #  1 ,  Shang-Xin Liu  #  1 ,  Bo-Yu Yuan  1  3 ,  Yi-Ling Luo  1 ,  Wen-Ting Du  1 ,  Chao-Bo Lei  1 ,  Yong-Zhan Nie  4 ,  Mu-Sheng Zeng  5 ,  Qian Zhong  6
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2. Institute of Medical Research, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 3. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 4. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, Shaanxi, China.
  • 5. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 6. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 40615663 DOI: 10.1038/s41418-025-01536-1
Abstract

Despite advancements of diagnosis and multimodality therapies in esophageal squamous-cell carcinoma (ESCC), the survival is still unsatisfactory. Therefore, it is urgent to identify novel targets for efficient therapeutic strategies. Herein, we identify a fusion gene between PLEKHA1 and TACC2 generated by chromosomal rearrangement by performing RNA Sequencing from ESCC tissues. PLEKHA1-TACC2 transcripts are present in ESCC (66/404, 16.3%) and head and neck squamous cell carcinoma (58/402, 14.4%) tissues, correlated with poor prognosis of patients. Mechanistically, the fusion proteins upregulate the EphA2/Akt/MMP2 signaling pathway and promote vascular mimicry formation by reducing the ubiquitylation of EphA2. Moreover, EphA2 inhibitors dasatinib and ALW II-41-27 remarkably suppress the progression of tumors expressing PLEKHA1-TACC2 in vivo. Functionally, PLEKHA1-TACC2 fusion and Trp53 deletion significantly increases tumor incidence, tumor multiplicity, and mouse mortality in transgenic ESCC mouse model, which could be suppressed by regorafenib, a EphA2 inhibitor approved by FDA in solid tumors. Together, our data indicate that PLEKHA1-TACC2 fusion protein has oncogenic activities and serves as a promising prognosis marker and therapeutic target.

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