AI Article Synopsis

  • The study investigates how changes in energy production pathways affect the spread of breast cancer cells in a mouse model, particularly focusing on the role of mitochondrial function.
  • Cells with severely compromised respiration could not form primary tumors unless they received healthy mitochondria from their environment, suggesting that mitochondrial health is crucial for tumor initiation.
  • The results indicate that while some cancer cells can adapt and metastasize with limited mitochondrial function, effective oxidative phosphorylation (OXPHOS) is necessary for successful tumor formation and spread.

Article Abstract

Background: Fast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.

Methods: 4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.

Results: OXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρD5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.

Conclusion: In summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094293PMC
http://dx.doi.org/10.3389/fonc.2024.1362786DOI Listing

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