Publication Date
5-1-2022
Journal
Nature
DOI
10.1038/s41586-022-04758-2
PMID
35585241
PMCID
PMC9888363
PubMedCentral® Posted Date
1-31-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Animals, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cell Proliferation, Disease Progression, Female, Gene Silencing, Humans, Mice, Neoplasm Metastasis, Phosphoglycerate Dehydrogenase, Serine
Abstract
Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer cells and silencing PHGDH in primary tumors increases metastasis formation. Mechanistically, PHGDH protein interacts with the glycolytic enzyme phosphofructokinase (PFK) and the loss of this interaction activates the hexosamine – sialic acid pathway, which provides precursors for protein glycosylation. Consequently, aberrant protein glycosylation including increased sialylation of integrin αvβ3 occurs, which potentiates cell migration and invasion. Inhibition of sialic acid metabolism counteracts the metastatic capacity of PHGDH low cancer cells. In conclusion, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. Thus, the presence of PHDGH heterogeneity in primary tumors may be considered a sign of tumor aggressiveness.
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