 PHGDH heterogeneity potentiates cancer cell dissemination and metastasisMatteo Rossi,
Patricia Altea-Manzano,
Margherita Demicco,
Ginevra Doglioni,
Laura Bornes,
Marina Fukano,
Anke Vandekeere,
Alejandro M. Cuadros,
Juan Fernández-García,
Carla Riera-Domingo,
Cristina Jauset,
Mélanie Planque,
H. Furkan Alkan,
David Nittner,
Dongmei Zuo,
Lindsay A. Broadfield,
Sweta Parik,
Antonino Alejandro Pane,
Francesca Rizzollo,
Gianmarco Rinaldi,
Tao Zhang,
Shao Thing Teoh,
Arin B. Aurora,
Panagiotis Karras,
Ines Vermeire,
Dorien Broekaert,
Joke Van Elsen,
Maximilian M. L. Knott,
Martin F. Orth,
Sofie Demeyer,
Guy Eelen,
Lacey E. Dobrolecki,
Ayse Bassez,
Thomas Van Brussel,
Karl Sotlar,
Michael T. Lewis,
Harald Bartsch,
Manfred Wuhrer,
Peter van Veelen,
Peter Carmeliet,
Jan Cools,
Sean J. Morrison,
Jean-Christophe Marine,
Diether Lambrechts,
Massimiliano Mazzone,
Gregory J. Hannon,
Sophia Y. Lunt,
Thomas G. P. Grünewald,
Morag Park,
Jacco van Rheenen and
Sarah-Maria Fendt ()
Nature, 2022, vol. 605, issue 7911, 747-753 Abstract: 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 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. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:605:y:2022:i:7911:d:10.1038_s41586-022-04758-2 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-04758-2 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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