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<p>The findings demonstrate that upregulation of CCL2 constitutes a significant risk factor for metastatic progression in esophageal squamous cell carcinoma (ESCC), with CCL2 facilitating metastasis through TWIST1-mediated induction of a hybrid epithelial-mesenchymal transition (EMT) phenotype. Notably, inhibition of TWIST1 alone elicits a compensatory activation of JUNB via the PI3K/AKT signaling pathway, thereby preserving EMT plasticity and metastatic potential. To address this adaptive resistance, we developed a dual-targeting strategy aimed at concurrently suppressing TWIST1 and JUNB, which resulted in a synergistic attenuation of metastatic characteristics. In vivo validation using zebrafish and murine models indicated that this combined inhibition restricts metastatic potential. The study concludes that the interplay between TWIST1 and JUNB underpins adaptive resistance mechanisms in CCL2-high ESCC by sustaining a hybrid EMT state, and that dual targeting of these factors disrupts this process, representing a promising therapeutic approach to suppresses CCL2-driven metastasis in preclinical models.</p>

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Co-targeting TWIST1 and JUNB suppresses CCL2-induced cell motility and hybrid EMT in ESCC models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Zihang Ling,
  • Wenxin Mu,
  • Dongyao Wang,
  • Chao Lv,
  • Bin Cheng,
  • Xiaoan Tao

摘要

The findings demonstrate that upregulation of CCL2 constitutes a significant risk factor for metastatic progression in esophageal squamous cell carcinoma (ESCC), with CCL2 facilitating metastasis through TWIST1-mediated induction of a hybrid epithelial-mesenchymal transition (EMT) phenotype. Notably, inhibition of TWIST1 alone elicits a compensatory activation of JUNB via the PI3K/AKT signaling pathway, thereby preserving EMT plasticity and metastatic potential. To address this adaptive resistance, we developed a dual-targeting strategy aimed at concurrently suppressing TWIST1 and JUNB, which resulted in a synergistic attenuation of metastatic characteristics. In vivo validation using zebrafish and murine models indicated that this combined inhibition restricts metastatic potential. The study concludes that the interplay between TWIST1 and JUNB underpins adaptive resistance mechanisms in CCL2-high ESCC by sustaining a hybrid EMT state, and that dual targeting of these factors disrupts this process, representing a promising therapeutic approach to suppresses CCL2-driven metastasis in preclinical models.