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Targeting PTBP3-Mediated Alternative Splicing of COX11 Induces Cuproptosis for Inhibiting Gastric Cancer Peritoneal

Yajing Zhou1, Chao Dong1, Xiaochun Shen2

  • 1Department of General Surgery, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, Jiangsu Province, 215031, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 24, 2025
PubMed

Insights

This study reveals that elevated PTBP3 expression promotes gastric cancer peritoneal metastasis by altering COX11 splicing, impacting copper metabolism and cell survival. Targeting this pathway offers new therapeutic avenues for advanced gastric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Aberrant splicing events are crucial in tumor progression, but their role in gastric cancer peritoneal metastasis (GCPM) remains understudied.
  • Splicing factors and their specific targets in GCPM require comprehensive investigation.

Purpose of the Study:

  • To investigate the role and mechanism of PTBP3 in promoting peritoneal metastasis of gastric cancer.
  • To identify therapeutic strategies targeting PTBP3-mediated splicing events and copper metabolism in GCPM.

Main Methods:

  • Differential expression analysis of PTBP3 in primary and metastatic gastric cancer tissues.
  • In vitro studies using gastric cancer cells and patient-derived organoids (PDO) to assess PTBP3 function.
  • Full-length transcriptome sequencing to identify PTBP3 target genes and splicing events.
  • Development and testing of antisense oligonucleotide (ASO) drugs targeting COX11 mRNA.
  • PDO-based xenograft models to evaluate therapeutic efficacy of ASO drugs combined with copper ionophores.

Main Results:

  • PTBP3 is significantly overexpressed in GCPM tissues and correlates with poor prognosis.
  • PTBP3 mediates exon 4 skipping in COX11, producing shorter transcripts that impair COX11 function and reduce mitochondrial copper.
  • This leads to evasion of cuproptosis, promoting tumor cell survival and proliferation in GCPM.
  • ASO drugs targeting short COX11 transcripts effectively degrade mRNA and disrupt copper homeostasis.
  • Combination therapy with ASO drugs and copper ionophores induces mitochondrial copper overload, triggering cell death via proteotoxic stress and cuproptosis in PDO models.

Conclusions:

  • PTBP3-mediated COX11 exon 4 skipping is a key driver of gastric cancer peritoneal metastasis.
  • Targeting PTBP3-driven splicing alterations and copper metabolism presents a promising therapeutic strategy for GCPM.
  • This research elucidates a novel mechanism linking splicing, copper homeostasis, and cancer progression.
Keywords:
alternative splicingantisense oligonucleotide drugscuproptosisgastric cancer peritoneal metastasispatient‐derived organoids‐based xenograft

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