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

Zihang Ling1,2, Wenxin Mu1,2, Dongyao Wang1,2

  • 1Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, PR China.

Communications Biology
|July 8, 2026
PubMed

Insights

High CCL2 levels drive esophageal cancer metastasis via TWIST1 and JUNB. Targeting both TWIST1 and JUNB synergistically blocks metastasis, offering a promising therapeutic strategy for esophageal squamous cell carcinoma (ESCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Upregulation of CCL2 is a significant risk factor for metastatic progression in esophageal squamous cell carcinoma (ESCC).
  • CCL2 promotes metastasis by inducing a hybrid epithelial-mesenchymal transition (EMT) phenotype, mediated by TWIST1.
  • Inhibition of TWIST1 can lead to compensatory activation of JUNB, preserving metastatic potential.

Purpose of the Study:

  • To investigate the role of the TWIST1-JUNB interplay in adaptive resistance to metastasis in CCL2-high ESCC.
  • To develop and evaluate a dual-targeting strategy against TWIST1 and JUNB to overcome adaptive resistance and suppress metastasis.

Main Methods:

  • Investigated the molecular mechanisms of CCL2-driven metastasis in ESCC, focusing on TWIST1 and JUNB.
  • Developed a dual-targeting strategy to inhibit both TWIST1 and JUNB concurrently.
  • Validated the efficacy of the dual-targeting strategy in preclinical zebrafish and murine models.

Main Results:

  • CCL2 facilitates ESCC metastasis through TWIST1-induced hybrid EMT.
  • TWIST1 inhibition triggers compensatory JUNB activation via PI3K/AKT, maintaining metastatic potential.
  • Dual targeting of TWIST1 and JUNB synergistically reduced metastatic characteristics in vitro and in vivo.
  • Combined inhibition effectively restricted metastatic potential in zebrafish and murine models.

Conclusions:

  • The TWIST1-JUNB axis is crucial for adaptive resistance in CCL2-high ESCC by sustaining a hybrid EMT state.
  • Dual inhibition of TWIST1 and JUNB disrupts this adaptive resistance mechanism.
  • This dual-targeting approach shows promise for suppressing CCL2-driven metastasis in ESCC preclinical models.

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