Divergent use of metabolic fluxes in breast cancer metastasis

Breast cancers can metastasize to many organs. But how do disseminated cells from a primary tumor adapt to distal tissues? Here we combined metabolomics, flux measurements, and mathematical modeling to study metabolic fluxes in breast cancer cells adapted to home to different organs. We found that lung-homing cells maintain 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 to pyruvate dehydrogenase gene expression, which also correlates with lung metastases in patients with breast cancer. Surprisingly, this strong Warburg effect does not necessarily increase cellular growth rate, suggesting that lactate secretion may be a trait under selection in lung metastasis. Our results stress that metabolic fluxes may not correlate with metabolic intermediates, a finding relevant for metastatic tropism.