TY - JOUR
T1 - PHGDH heterogeneity potentiates cancer cell dissemination and metastasis
AU - Rossi, Matteo
AU - Altea-Manzano, Patricia
AU - Demicco, Margherita
AU - Doglioni, Ginevra
AU - Bornes, Laura
AU - Fukano, Marina
AU - Vandekeere, Anke
AU - Cuadros, Alejandro M.
AU - Fernández-García, Juan
AU - Riera-Domingo, Carla
AU - Jauset, Cristina
AU - Planque, Mélanie
AU - Alkan, H. Furkan
AU - Nittner, David
AU - Zuo, Dongmei
AU - Broadfield, Lindsay A.
AU - Parik, Sweta
AU - Pane, Antonino Alejandro
AU - Rizzollo, Francesca
AU - Rinaldi, Gianmarco
AU - Zhang, Tao
AU - Teoh, Shao Thing
AU - Aurora, Arin B.
AU - Karras, Panagiotis
AU - Vermeire, Ines
AU - Broekaert, Dorien
AU - Elsen, Joke Van
AU - Knott, Maximilian M.L.
AU - Orth, Martin F.
AU - Demeyer, Sofie
AU - Eelen, Guy
AU - Dobrolecki, Lacey E.
AU - Bassez, Ayse
AU - Brussel, Thomas Van
AU - Sotlar, Karl
AU - Lewis, Michael T.
AU - Bartsch, Harald
AU - Wuhrer, Manfred
AU - Veelen, Peter van
AU - Carmeliet, Peter
AU - Cools, Jan
AU - Morrison, Sean J.
AU - Marine, Jean Christophe
AU - Lambrechts, Diether
AU - Mazzone, Massimiliano
AU - Hannon, Gregory J.
AU - Lunt, Sophia Y.
AU - Grünewald, Thomas G.P.
AU - Park, Morag
AU - Rheenen, Jacco van
AU - Fendt, Sarah Maria
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/5/26
Y1 - 2022/5/26
N2 - 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 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 Phgdhlow 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 αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow 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.
AB - 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 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 Phgdhlow 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 αvβ3, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdhlow 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.
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U2 - 10.1038/s41586-022-04758-2
DO - 10.1038/s41586-022-04758-2
M3 - Article
C2 - 35585241
AN - SCOPUS:85130254559
SN - 0028-0836
VL - 605
SP - 747
EP - 753
JO - Nature
JF - Nature
IS - 7911
ER -