PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

Rossi, M.; Altea-Manzano, P.; Demicco, M.; Doglioni, G.; Bornes, L.; Fukano, M.; Vandekeere, A.; Cuadros, A.M.; Fernandez-Garcia, J.; Riera-Domingo, C.; Jauset, C.; Planque, M.; Alkan, H.F.; Nittner, D.; Zuo, D.M.; Broadfield, L.A.; Parik, S.; Pane, A.A.; Rizzollo, F.; Rinaldi, G.; Zhang, T.; Teoh, S.T.; Aurora, A.B.; Karras, P.; Vermeire, I.; Broekaert, D.; Elsen, J. van; Knott, M.M.L.; Orth, M.F.; Demeyer, S.; Eelen, G.; Dobrolecki, L.E.; Bassez, A.; Brussel, T. van; Sotlar, K.; Lewis, M.T.; Bartsch, H.; Wuhrer, M.; Veelen, P. van; Carmeliet, P.; Cools, J.; Morrison, S.J.; Marine, J.C.; Lambrechts, D.; Mazzone, M.; Hannon, G.J.; Lunt, S.Y.; Grunewald, T.G.P.; Park, M.; Rheenen, J. van; Fendt, S.M.

doi:doi:10.1038/s41586-022-04758-2

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs(1). Genetic, transcriptional and translational heterogeneity contributes to this dynamic process(2,3). Metabolic heterogeneity has also been observed(4), yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdh(low) cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein...Show moreCancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs(1). Genetic, transcriptional and translational heterogeneity contributes to this dynamic process(2,3). Metabolic heterogeneity has also been observed(4), yet its role in cancer progression is less explored. Here we find that the loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumours of patients with breast cancer is associated with decreased metastasis-free survival time. In mice, circulating tumour cells and early metastatic lesions are enriched with Phgdh(low) cancer cells, and silencing Phgdh in primary tumours increases metastasis formation. Mechanistically, Phgdh interacts with the glycolytic enzyme phosphofructokinase, and the loss of this interaction activates the hexosamine-sialic acid pathway, which provides precursors for protein glycosylation. As a consequence, aberrant protein glycosylation occurs, including increased sialylation of integrin alpha(v)beta(3), which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdh(low) cancer cells. In conclusion, although 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 tumours could be considered a sign of tumour aggressiveness.Show less

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PHGDH heterogeneity potentiates cancer cell dissemination and metastasis