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Novel Evolutionarily Conserved Oncogene COA4 is Driven by KRAS Mutant and Promotes Cancer Metastasis Through Dual

Xingzhao Ji1,2,3, Weiying Zhang2,4, Fuyuan Xue1

  • 1Shandong Provincial Key Medical and Health Laboratory of cell metabolism, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 12, 2025
PubMed

Insights

Researchers identified COA4 as a key driver of KRAS-mutant lung cancer metastasis. Targeting COA4, which regulates both cytochrome c oxidase (COX) and CDC42, offers a promising therapeutic strategy for KRAS-mutant lung adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Metastasis is the primary cause of cancer mortality, with limited treatments for KRAS-mutant lung adenocarcinoma.
  • KRAS mutations are common drivers in lung cancer, but effective anti-metastatic therapies are scarce.

Purpose of the Study:

  • To identify novel regulators of KRAS-mutant lung adenocarcinoma metastasis.
  • To elucidate the mechanism by which COA4 promotes metastasis and evaluate its therapeutic potential.

Main Methods:

  • Utilized genetically engineered mouse models (KRASG12D/-;TP53-/-;COA4-/-), clinical specimens, and organoid models.
  • Employed RNA sequencing, xenograft assays, Seahorse metabolic profiling, and subcellular fractionation.
  • Investigated the roles of COA4 in cytochrome c oxidase (COX) activity and CDC42 activation.

Main Results:

  • COA4 is overexpressed in KRAS-mutant tumors, correlating with increased metastasis and poor prognosis.
  • COA4 deficiency significantly reduced lymph node metastasis; its overexpression enhanced metastatic capabilities.
  • COA4 regulates mitochondrial COX activity and cytosolic CDC42 activation, driving metastasis independently of proliferation.

Conclusions:

  • COA4 is a critical KRASG12C/D effector that promotes lung adenocarcinoma metastasis via dual regulation of COX and CDC42.
  • Targeting COA4, COX, oxidative phosphorylation, or CDC42 demonstrates therapeutic potential for KRASG12C/D-driven cancers.
  • The dual function of COA4 in metastasis is evolutionarily conserved, highlighting its fundamental role in cancer progression.
Keywords:
COA4KRAS, metastasisOXPHOSSaccharomyces cerevisiaecytochrome c oxidase

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