Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY We recently discovered that low, rather than high, expression of phosphoglycerate dehydrogenase (PHGDH) in the serine biosynthesis pathway is indicative of metastasis in triple negative breast cancer (TNBC) primary tumors. Our preliminary experiments indicate that low PHGDH expression results in upregulation of the sialic acid biosynthesis pathway, which in turn activates cellular programs required for metastasis. However, catalytic inhibition of PHGDH does not increase sialic acid biosynthesis or metastasis, suggesting a non-catalytic role for PHGDH. This project aims to: 1) investigate this non-canonical role of PHGDH in modulating sialic acid biosynthesis, 2) decipher the metabolic rewiring that dictates low-PHGDH activation of sialic acid metabolism, and 3) elucidate the mechanism of low PHGDH, high sialic acid metabolism-driven metastasis. To confirm non- canonical PHGDH function, we will knock out other serine biosynthetic genes to show that it is not inhibition of serine biosynthesis that drives sialic acid upregulation and metastasis. We will investigate PHGDH protein- protein interactions and subcellular localization of PHGDH protein to further probe its non-canonical function. Metabolic rewiring in low-PHGDH cells will be elucidated in detail using mass spectrometry methods. We will also overexpress genes in metabolic pathways branching from glycolysis to determine whether sialic acid metabolic flux is sensitive to diversion of carbon flux into competing pathways. Finally, our preliminary data links high sialic acid metabolic flux to increased phosphorylation of EMT markers and p38 and c-SRC as drivers of metastasis. We will study the importance of p38 and SRC phosphorylation in potentiating metastasis and investigate whether this link is mediated by increased sialic acid flux or sialylation at the cell surface. Our overall objective is to elucidate the mechanism of low PHGDH driven sialic acid upregulation as an enabler of breast cancer metastasis, which will lead to new biomarkers (low PHGDH, high sialic acid) for metastasis and development of novel therapeutic strategies for metastatic TNBC.
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