Divergent use of metabolic fluxes in breast cancer metastasis

Breast cancers can metastasize to many organs. But how do the cells disseminated from a primary tumor adapt to fit distal tissues? Here we combined metabolomics, flux measurements and mathematical modeling to study the metabolic fluxes in human breast cancer cells adapted to home to different organs. We found that lung-homing cells maintain a high glycolytic flux despite low levels of glycolytic intermediates, by constitutively activating a pathway sink into lactate. Their distinct behavior - a strong Warburg effect - has a gene expression signature: a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) gene expression, which also correlates with lung metastases in patients with breast cancer. Surprisingly, a strong Warburg effect does not necessarily increase cellular growth rate, suggesting that lactate secretion may be a trait under selection in breast cancer lung metastasis.