Metabolic profiling reveals a dependency of human metastatic breast cancer on mitochondrial serine and one-carbon unit metabolism Journal Article
| Authors: | Li, A. M.; Ducker, G. S.; Li, Y.; Seoane, J. A.; Xiao, Y.; Melemenidis, S.; Zhou, Y.; Liu, L.; Vanharanta, S.; Graves, E. E.; Rankin, E. B.; Curtis, C.; Massagué, J.; Rabinowitz, J. D.; Thompson, C. B.; Ye, J. |
| Article Title: | Metabolic profiling reveals a dependency of human metastatic breast cancer on mitochondrial serine and one-carbon unit metabolism |
| 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 de novo 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. © 2020 American Association for Cancer Research. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; cancer growth; nonhuman; bone metastasis; cancer staging; outcome assessment; cell proliferation; mass spectrometry; mouse; animal experiment; animal model; practice guideline; renal cell carcinoma; adrenal cortex carcinoma; lung metastasis; brain metastasis; real time polymerase chain reaction; upregulation; metastasis potential; tumor growth; metastatic breast cancer; metabolomics; liquid chromatography-mass spectrometry; nucleotide metabolism; human; female; priority journal; article; ultra performance liquid chromatography; glycine hydroxymethyltransferase; mda-mb-231 cell line; serine hydroxymethyltransferase 2; mitochondrial serine and one carbon unit metabolism |
| Journal Title: | Molecular Cancer Research |
| Volume: | 18 |
| Issue: | 4 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-04-01 |
| Start Page: | 599 |
| End Page: | 611 |
| Language: | English |
| DOI: | 10.1158/1541-7786.Mcr-19-0606 |
| PUBMED: | 31941752 |
| PROVIDER: | scopus |
| PMCID: | PMC7127984 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 May 2020 -- Source: Scopus |
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