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PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

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 pro...

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Main Authors: Rossi, Matteo (Author) , Altea-Manzano, Patricia (Author) , Demicco, Margherita (Author) , Doglioni, Ginevra (Author) , Bornes, Laura (Author) , Fukano, Marina (Author) , Vandekeere, Anke (Author) , Cuadros, Alejandro M. (Author) , Fernández-García, Juan (Author) , Riera-Domingo, Carla (Author) , Jauset, Cristina (Author) , Planque, Mélanie (Author) , Alkan, H. Furkan (Author) , Nittner, David (Author) , Zuo, Dongmei (Author) , Broadfield, Lindsay A. (Author) , Parik, Sweta (Author) , Pane, Antonino A. (Author) , Rizzollo, Francesca (Author) , Rinaldi, Gianmarco (Author) , Zhang, Tao (Author) , Teoh, Shao Thing (Author) , Aurora, Arin B. (Author) , Karras, Panagiotis (Author) , Vermeire, Ines (Author) , Broekaert, Dorien (Author) , Elsen, Joke Van (Author) , Knott, Maximilian M. L. (Author) , Orth, Martin F. (Author) , Demeyer, Sofie (Author) , Eelen, Guy (Author) , Dobrolecki, Lacey E. (Author) , Bassez, Ayse (Author) , Brussel, Thomas Van (Author) , Sotlar, Karl (Author) , Lewis, Michael T. (Author) , Bartsch, Harald (Author) , Wuhrer, Manfred (Author) , Veelen, Peter van (Author) , Carmeliet, Peter (Author) , Cools, Jan (Author) , Morrison, Sean J. (Author) , Marine, Jean-Christophe (Author) , Lambrechts, Diether (Author) , Mazzone, Massimiliano (Author) , Hannon, Gregory J. (Author) , Lunt, Sophia Y. (Author) , Grünewald, Thomas G. P. (Author) , Park, Morag (Author) , Rheenen, Jacco van (Author) , Fendt, Sarah-Maria (Author)
Format: Article (Journal)
Language:English
Published: 2022
In: Nature
Year: 2022, Volume: 605, Issue: 7911, Pages: 747-753
ISSN:1476-4687
DOI:10.1038/s41586-022-04758-2
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41586-022-04758-2
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41586-022-04758-2
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Author Notes:Matteo 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 & Sarah-Maria Fendt
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Summary: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.
Item Description:Published online: 18 May 2022
Gesehen am 11.07.2022
Physical Description:Online Resource
ISSN:1476-4687
DOI:10.1038/s41586-022-04758-2

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