Metabolic Profiling Reveals a Dependency of Human Metastatic Breast Cancer on Mitochondrial Serine and One-Carbon Unit Metabolism. Author Albert Li, Gregory Ducker, Yang Li, Jose Seoane, Yiren Xiao, Stavros Melemenidis, Yiren Zhou, Ling Liu, Sakari Vanharanta, Edward Graves, Erinn Rankin, Christina Curtis, Joan Massagué, Joshua Rabinowitz, Craig Thompson, Jiangbin Ye Publication Year 2020 Type Journal Article Abstract Breast cancer is the most common cancer among American women and a major cause of mortality. To identify metabolic pathways as potential targets to treat metastatic breast cancer, we performed metabolomics profiling on the breast cancer cell line MDA-MB-231 and its tissue-tropic metastatic subclones. Here, we report that these subclones with increased metastatic potential display an altered metabolic profile compared with the parental population. In particular, the mitochondrial serine and one-carbon (1C) unit pathway is upregulated in metastatic subclones. Mechanistically, the mitochondrial serine and 1C unit pathway drives the faster proliferation of subclones through enhanced purine biosynthesis. Inhibition of the first rate-limiting enzyme of the mitochondrial serine and 1C unit pathway, serine hydroxymethyltransferase (SHMT2), potently suppresses proliferation of metastatic subclones in culture and impairs growth of lung metastatic subclones at both primary and metastatic sites in mice. Some human breast cancers exhibit a significant association between the expression of genes in the mitochondrial serine and 1C unit pathway with disease outcome and higher expression of SHMT2 in metastatic tumor tissue compared with primary tumors. In addition to breast cancer, a few other cancer types, such as adrenocortical carcinoma and kidney chromophobe cell carcinoma, also display increased SHMT2 expression during disease progression. Together, these results suggest that mitochondrial serine and 1C unit metabolism plays an important role in promoting cancer progression, particularly in late-stage cancer. IMPLICATIONS: This study identifies mitochondrial serine and 1C unit metabolism as an important pathway during the progression of a subset of human breast cancers. Keywords Animals, Mice, Humans, Female, Breast Neoplasms, Metabolomics, Mitochondria, Carbon, Serine Journal Mol Cancer Res Volume 18 Issue 4 Pages 599-611 Date Published 2020 Apr ISSN Number 1557-3125 DOI 10.1158/1541-7786.MCR-19-0606 Alternate Journal Mol Cancer Res PMCID PMC7127984 PMID 31941752 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML