Metabolic reprogramming in disseminated cells

Access through your institution Buy or subscribe 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. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online

access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which

are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * 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) Download references

Authors * Gemma K. Alderton View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE Alderton, G. Metabolic reprogramming in disseminated cells. _Nat Rev Cancer_ 14, 703 (2014). https://doi.org/10.1038/nrc3842 Download citation * Published: 16 October 2014 * Issue

Date: November 2014 * DOI: https://doi.org/10.1038/nrc3842 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative