The Ratio of Key Metabolic Transcripts Is a Predictive Biomarker of Breast Cancer Metastasis to the Lung

Abstract

Breast cancer is a disease marked by cellular diversity. Primary breast tumors can spread to and colonize multiple organ sites, forming metastases. Understanding the factors that drive metastatic tropism and being able to predict metastasis to specific organs a priori remains a challenge. In this study, we investigated how rewired metabolism underlying organ-specific metastasis in breast cancer could help identify strategies to improve the treatment and prevention of metastatic disease. We found that parental breast cancer cells and metastases in the brain and lung each had a distinct, heritable metabolic flux signature. Lung metastatic cells maintained particularly high glycolytic flux by activating a pathway sink into lactate, characterized by a high ratio of lactate dehydrogenase (LDH) to pyruvate dehydrogenase (PDH) gene expression. This elevated LDH/PDH ratio also correlated with lung metastasis in patients with breast cancer. We employed feature classification models on patient data and found that expression of genes taken individually or collectively were unable to predict metastatic tropism. However, the LDH/PDH ratio was a significant predictor of metastasis to the lung specifically. Importantly, alterations of LDH/PDH in the primary tumor in cell lines and patients indicated future lung metastases, such that this ratio was a bona fide predictor. Lung metastases in pancreatic cancer models also exhibited the same metabolic flux alteration, suggesting that lactate production may be a convergent phenotype in lung metastasis across cancer types. Together, these analyses highlight the essential role that metabolism plays in organ-specific cancer metastasis and identify a putative biomarker for predicting lung metastasis in breast cancer patients.