AMBRA1 drives gastric cancer progression through regulation of tumor plasticity

Front Immunol. 2024 Dec 10:15:1494364. doi: 10.3389/fimmu.2024.1494364. eCollection 2024.

Abstract

Background: Stomach adenocarcinoma (STAD) is an aggressive malignancy characterized by high tumor plasticity and heterogeneity. This study investigates the role of Autophagy and Beclin 1 Regulator 1 (AMBRA1) in regulating tumor plasticity in STAD progression.

Methods: Combined with clinical data, the pan-cancer analysis of AMBRA1 was performed to analyze the role of AMBRA1 in STAD. Western blot, Flow Cytometry (FCM) assay, trans-well assay, wound healing assay, MTT, Reactive Oxygen Species (ROS) assay, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) and staining were performed to study the effects of AMBRA1 in AGS human gastric cancer cells. An AGS gastric cancer xenograft model was constructed to further verify the role of AMBRA1 in the development of STAD.

Results: AMBRA1 overexpression correlated with poor overall survival in STAD and was positively associated with T cell CD4+ infiltration. High AMBRA1 expression also indicated worse prognosis in patients with high cancer-associated fibroblast infiltration. AMBRA1 depletion suppressed STAD cell proliferation, migration, and invasion in vitro. Mechanistically, AMBRA1 knockdown induced G1/S cell cycle arrest and triggered cellular senescence through epigenetic alterations, including changes in H3K9me3 levels. AMBRA1 inhibition also sensitized STAD cells to chemotherapeutic agents. In vivo studies confirmed the tumor-suppressive effects of AMBRA1 loss, resulting in reduced tumor growth and increased cellular senescence.

Conclusions: Our findings uncover an oncogenic role for AMBRA1 in STAD. Targeting AMBRA1 may induce tumor cell senescence, apoptosis, and potentiate anti-tumor immunity, providing a rationale for developing AMBRA1-targeted precision therapies to improve clinical outcomes in STAD patients.

Keywords: AMBRA1; cell cycle; gastric cancer; senescence; tumor plasticity.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cellular Senescence / genetics
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Prognosis
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / immunology
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Tumor Microenvironment / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • AMBRA1 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the National Natural Science Foundation of China (No. 82204482), the Guangdong Basic and Applied Basic Research Foundation (China) (No. 2024A1515010167), Guangzhou Basic and Applied Basic Research Foundation (China) (2023A03J0616 and 2024A04J9918), Young Elite Scientists Sponsorship Program by CACM (China) (No. 2021-QNRC2-B22), Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province (2022SXHD0003), Key Laboratory of Sichuan Province for Traditional Chinese Medicine Regimen and Health & Key Laboratory of State Administration of Traditional Chinese Medicine for Scientific Research & Industrial Development of Traditional Chinese Medicine Regimen and Health (China) (GZ2022003) and the Start-up Research Foundation from Guangzhou Maritime University/Guangzhou Jiaotong University (under Preparation) (No. K42022103), the Science and Technology Development Fund, Macau S.A.R (FDCT) (File no. 0073/2023/RIA2 and 0060/2023/ITP2) and the Research Fund of University of Macau (File no. MYRG-GRG2023–00048-ICMS).