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Metastasis

Metabolic reprogramming in disseminated cells

Nature Reviews Cancer volume 14, page 703 (2014)Cite this article

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LeBleu et al. isolated green fluorescent protein (GFP)-positive primary, circulating and metastatic tumour cells from mice implanted with GFP-labelled 4T1 mammary epithelial cancer cells that form tumours and metastasize to the lung. Gene expression profiling revealed that oxidative phosphorylation pathway genes were the most differentially regulated in circulating tumour cells (CTCs) compared with primary tumour cells. Further analyses revealed that certain genes were specifically upregulated in the CTCs, especially those associated with mitochondrial biogenesis and oxidative phosphorylation. Peroxisome proliferator-activated receptor-γ co-activator 1α (PPARGC1A; also known as PGC1A) encodes a transcriptional co-activator that promotes mitochondrial biogenesis, ATP production and metabolic reprogramming during stress and its expression was the highest among all genes in the CTCs. Consistently, the authors found that CTCs from 4T1 tumours, as well as CTCs from GFP-labelled B16F10 mouse melanomas and MDA-MB-231 human breast xenograft tumours, had increased amounts of mitochondrial DNA and ATP, as well as increased basal respiration rate and mitochondrial oxygen consumption rate, compared with matched primary tumour cells.

Interestingly, comparing primary and metastatic tumour cells from the 4T1 mouse model revealed limited differences in the expression of genes associated with mitochondria biogenesis and oxidative phosphorylation, indicating that the changes in CTCs are reversible. The metabolic gene expression changes in CTCs occurred concomitantly with epithelial–mesenchymal transition (EMT); gene expression in metastatic tumour cells (which have presumably undergone mesenchymal–epithelial transition (MET)) partially returned to that of primary tumour cells. This indicated that the metabolic changes of CTCs were coupled with a mesenchymal phenotype. Indeed, the authors found that cancer cells with a mesenchymal phenotype had significantly higher levels of PPARGC1α than cancer cells without mesenchymal markers. Moreover, PPARGC1α expression was induced as tumour cells were moved into an oxygenated environment from hypoxia — as occurs when cells become migratory — and in parallel, the expression of Twist1 (which encodes an EMT transcription factor) was induced. However, knockdown of either TWIST1 or PPARGC1α expression had no effect on the other or on the transcriptional programmes they induce, indicating that EMT and PPARGC1α-mediated metabolic reprogramming occur independently in response to the same microenvironmental conditions.

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References

  1. LeBleu, V. S. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nature Cell Biol. http://dx.doi.org/10.1038/ncb3039 (2014)

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  1. Gemma K. Alderton
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Alderton, G. Metabolic reprogramming in disseminated cells. Nat Rev Cancer 14, 703 (2014). https://doi.org/10.1038/nrc3842

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