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Elizabeth M O’Day,1,2 Greg E Idos,3 Collin Hill,4 Joan W Chen,5 Gerhard Wagner1 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; 2Olaris Therapeutics, Cambridge, MA 02138, USA; 3Division of Gastroenterology and Liver Disease, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA; 4PerkinElmer, Waltham, MA 02451, USA; 5Rancho Biosciences, San Diego, CA 92127, USA Background: Cancer cells have altered bioenergetics, which contributes to their ability to proliferate, survive in unusual microenvironments, and invade other tissues. Changes in glucose metabolism can have pleomorphic effects on tumor cells. Methods: To investigate potential mechanisms responsible for the increased malignancy associated with altered glucose metabolism, we used an unbiased nuclear magnetic resonance spectroscopy screening method to identify glucose metabolites differentially produced in a highly malignant human triple-negative breast cancer (TNBC) cell line (BPLER) and a less malignant isogenic TNBC cell line (HMLER). Results: N-acetylneuraminic acid (Neu5Ac), the predominant sialic acid derivative in mammalian cells, which forms the terminal sugar on mucinous cell surface glycoproteins, was the major glucose metabolite that differed. Neu5Ac was ~7-fold more abundant in BPLER than HMLER. Loss of Neu5Ac by enzymatic removal or siRNA knockdown of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS), which activates cellular sialic acids for glycoprotein conjugation, had no significant effect on cell proliferation, but decreased the ability of BPLER to invade through a basement membrane. Conversely, overexpressing CMAS in HMLER increased invasivity. TNBCs in The Cancer Genome Atlas also had significantly more CMAS copy number variations and higher mRNA expression than non-TNBC, which have a better prognosis. CMAS knockdown in BPLER ex vivo blocked xenograft formation in mice. Conclusion: Neu5Ac is selectively highly enriched in aggressive TNBC, and CMAS, the enzyme required for sialylation, may play an important role in TNBC tumor formation and invasivity. Keywords: triple-negative breast cancer, metabolism, invasion, cytidine monophosphate N-acetylneuraminic acid, sialic acid, NMR spectroscopy, metabolomics |
