Low Phosphoglycerate Dehydrogenase Levels Drive Metastatic Dissemination

Heterogeneity at the level of genetic, transcriptional, and translational differences between cells within a tumor impacts tumor biology and response to therapy, but the degree to which metabolic heterogeneity contributes to disease progression remains less characterized. Focusing on the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH), which is overexpressed or amplified in the majority of triple-negative breast cancers, Rossi, Altea-Manzano, and colleagues assessed patient samples of invasive human breast ductal carcinoma, noting that patients with heterogeneous or low PHGDH expression had significantly reduced metastasis-free survival compared with homogeneous and high PHGDH expression, as well as significantly lower expression of PHGDH in metastases compared with primary tumors. Supporting the role of PHGDH in early metastasis, genetic knockdown of Phgdh in orthotopically injected murine mammary cancer cells followed by intravital imaging demonstrated increased migratory behavior and lung metastatic burden. Coculture assays suggested that neighboring endothelial cells secrete factors that diminish PHGDH expression in tumor cells, and integration of transcriptomic and proteomic analyses of murine cancer cells with low PHGDH expression, following endothelial cell coculture or Phgdh knockdown, indicated enrichment in pathways involved in epithelial–mesenchymal transition, extracellular matrix remodeling, and integrin signaling. Notably, Phgdh knockdown activated the hexosamine–sialic acid pathway, promoting sialylation of proteins including integrin α_vβ₃, which supports invasion and migration. Inhibition of integrin α_vβ₃ signaling through blocking antibodies or genetic or pharmacologic inhibition of sialylation reversed the invasive phenotype of cancer cells following Phgdh loss in vitro and in vivo. Mechanistically, PHGDH was found to interact with the glycolytic enzyme that competes with the hexosamine–sialic acid pathway for the metabolite fructose-6-phosphate, revealing that loss of PHGDH protein, but not canonical PHGDH catalytic activity, promotes a metabolic switch that favors aberrant sialylation of a critical mediator of metastasis. Together, this work uncovers a noncanonical role for PHGDH, suggesting that tumors with heterogeneous or low PHGDH expression are primed for metastatic dissemination.

Rossi M, Altea-Manzano P, Demicco M, Doglioni G, Bornes L, Fukano M, et al. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature 2022;605:747–53.

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