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Updated: Jun 12, 2026

Development of Compendium for Esophageal Squamous Cell Carcinoma
03:36

Development of Compendium for Esophageal Squamous Cell Carcinoma

Published on: April 12, 2024

Inhibiting METTL3 synergizes with Notch blockade to treat ESCC by targeting cancer stemness via m6A-JAG2

Jingjing Duan1, Yingying Jin1, Yue Chen1

  • 1Department of Gastrointestinal Medical Oncology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Tianjin Medical University Cancer Institute and Hospital, Huan huxi Road, Tianjin, 300060, China.

Journal of Gastroenterology
|June 11, 2026
PubMed
Abstract

Insights

METTL3 enhances esophageal cancer stemness via m6A modification of JAG2, activating Notch signaling. Combining METTL3 inhibitors with Notch blockade offers a promising new therapy for esophageal squamous cell carcinoma (ESCC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Esophageal squamous cell carcinoma (ESCC) presents a significant therapeutic challenge with poor outcomes.
  • Cancer stemness drives ESCC progression and treatment resistance.
  • Existing stemness-targeting therapies, like Notch pathway inhibition, have limited clinical success.

Purpose of the Study:

  • To investigate the role of METTL3-mediated m6A modification in regulating ESCC stemness.
  • To explore the therapeutic potential of combining METTL3 inhibitors with Notch blockade for ESCC treatment.

Main Methods:

  • Integrated multi-omics sequencing and functional validation.
  • Systematic investigation of the METTL3/JAG2/Notch axis using in vitro and in vivo models.
  • Elucidation of molecular mechanisms via m6A-RNA immunoprecipitation, RNA stability assays, and exosome characterization.

Main Results:

  • METTL3 upregulation in ESCC correlates with poor patient prognosis.
  • METTL3 promotes ESCC proliferation, migration, and stemness via m6A modification of JAG2 mRNA, stabilizing it through IGF2BP2.
  • This axis activates Notch signaling, upregulates stemness markers (SOX9, CD44), and promotes angiogenesis via JAG2.
  • Combined METTL3 inhibition and Notch blockade show synergistic anti-tumor efficacy in preclinical models.

Conclusions:

  • The METTL3/JAG2 axis is a key regulator of ESCC progression via IGF2BP2-dependent m6A modification and Notch signaling.
  • This study presents a novel therapeutic strategy combining METTL3 inhibition and Notch blockade for effective stemness-targeting in ESCC.
Keywords:
Esophageal squamous cell carcinomaMETTL3Notch inhibitorsStemnessm6A

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