DUSP5 suppresses esophageal squamous cell carcinoma by counteracting macrophage-derived AREG-ERK1/2 signaling and disrupting an oncogenic ERK1/2-ELK1-DUSP5 feedback circuitry

  • Cell Death Dis. 2026 Apr 10;17(1):498. doi: 10.1038/s41419-026-08641-0.
Xu Huang  #  1 ,  Wenyi Xu  #  1 ,  Runze You  #  1 ,  Junjie Kuang  #  2 ,  Kai Zhu  3 ,  Jun Li  4 ,  Jingzhang Li  2 ,  Yavuz Nuri Ertas  5  6 ,  Qiuhong Ma  7 ,  Maojin Tian  8 ,  Miao Lin  9
Affiliations
  • 1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Department of Oncology, Liuzhou People's Hospital, Guangxi Medical University, Liuzhou, Guangxi, China.
  • 3. Department of Nuclear, Liuzhou People's Hospital, Guangxi Medical University, Liuzhou, Guangxi, China.
  • 4. Cancer Center, Huizhou First Hospital, Huizhou, Guangdong, China.
  • 5. Department of Biomedical Engineering, Erciyes University, Kayseri, 38039, Türkiye. [email protected].
  • 6. Mini-invasive Interventional Therapy Center, Shanghai East Hospital, Tongji University, Shanghai, China. [email protected].
  • 7. Department of Clinical Laboratory, Zibo Central Hospital Affiliated to Binzhou Medical University, Zibo, Shandong, 255036, China. [email protected].
  • 8. Zibo Central Hospital Affiliated to Binzhou Medical University, Zibo, Shandong, 255036, China. [email protected].
  • 9. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41956999 DOI: 10.1038/s41419-026-08641-0
Abstract

Dual-specificity Phosphatase 5 (DUSP5) is a key regulator of the mitogen-activated protein kinase (MAPK) pathway, with established roles in various types of Cancer. However, its function in esophageal squamous cell carcinoma (ESCC) remains unclear. This study combines single-cell transcriptomics with in vitro and in vivo models to investigate the role of DUSP5 in ESCC. Single-cell RNA Sequencing revealed tumor-infiltrating myeloid populations, including Apolipoprotein C-positive (APOC⁺) macrophages, which interact with tumor cells via the amphiregulin-epidermal growth factor receptor (AREG-EGFR) axis, activating MAPK/extracellular signal-regulated kinase (ERK) signaling to promote tumor growth and immune modulation. We identified a prognostic gene signature linked to these macrophages. DUSP5 expression was downregulated in ESCC tissues, and its overexpression inhibited cell proliferation, induced senescence and Apoptosis, and suppressed migration and invasion. In mouse xenografts, overexpression of DUSP5 reduced tumor growth and metastasis. Mechanistically, DUSP5 inhibited ERK1/2 activation, and its tumor-suppressive effects were reversed by ERK1/2 activation. Moreover, ETS Like-1 protein (ELK1), an ERK1/2 downstream transcription factor, was identified as a negative regulator of DUSP5. In a carcinogen-induced model, DUSP5 knockout increased tumor burden, effects reversed by ERK1/2 inhibition. Our findings indicate that the DUSP5-ERK1/2-ELK1 signaling axis, modulated by tumor-infiltrating myeloid cells, contributes to ESCC progression and represents a promising source of biomarkers and therapeutic targets.

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