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<p>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 <i>PLEKHA1</i> and <i>TACC2</i> generated by chromosomal rearrangement by performing RNA sequencing from ESCC tissues. <i>PLEKHA1-TACC2</i> 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月5日

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  • Ting Yang,
  • Zhi-Rui Lin,
  • Tian-Liang Xia,
  • Shang-Xin Liu,
  • Bo-Yu Yuan,
  • Yi-Ling Luo,
  • Wen-Ting Du,
  • Chao-Bo Lei,
  • Yong-Zhan Nie,
  • Mu-Sheng Zeng,
  • Qian Zhong

摘要

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.