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PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

Author

Listed:
  • Matteo Rossi

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Patricia Altea-Manzano

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Margherita Demicco

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Ginevra Doglioni

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Laura Bornes

    (Oncode Institute, The Netherlands Cancer Institute)

  • Marina Fukano

    (University of Montreal
    McGill University
    McGill University)

  • Anke Vandekeere

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Alejandro M. Cuadros

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Juan Fernández-García

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Carla Riera-Domingo

    (VIB
    KU Leuven)

  • Cristina Jauset

    (University of Cambridge, Li Ka Shing Centre)

  • Mélanie Planque

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • H. Furkan Alkan

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • David Nittner

    (VIB-KU Leuven Center for Cancer Biology
    KU Leuven)

  • Dongmei Zuo

    (McGill University)

  • Lindsay A. Broadfield

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Sweta Parik

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Antonino Alejandro Pane

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Francesca Rizzollo

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Gianmarco Rinaldi

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Tao Zhang

    (Leiden University Medical Center)

  • Shao Thing Teoh

    (Michigan State University)

  • Arin B. Aurora

    (University of Texas Southwestern Medical Center)

  • Panagiotis Karras

    (KU Leuven
    VIB Center for Cancer Biology)

  • Ines Vermeire

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Dorien Broekaert

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Joke Van Elsen

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

  • Maximilian M. L. Knott

    (Institute of Pathology, Faculty of Medicine, LMU Munich)

  • Martin F. Orth

    (Institute of Pathology, Faculty of Medicine, LMU Munich)

  • Sofie Demeyer

    (VIB-KU Leuven)

  • Guy Eelen

    (KU Leuven
    VIB)

  • Lacey E. Dobrolecki

    (StemMed)

  • Ayse Bassez

    (VIB
    KU Leuven)

  • Thomas Van Brussel

    (VIB
    KU Leuven)

  • Karl Sotlar

    (University Hospital Salzburg, Paracelsus Medical University)

  • Michael T. Lewis

    (StemMed)

  • Harald Bartsch

    (Ludwig Maximilians University)

  • Manfred Wuhrer

    (Leiden University Medical Center)

  • Peter van Veelen

    (Leiden University Medical Center)

  • Peter Carmeliet

    (KU Leuven
    VIB
    Khalifa University of Science and Technology
    Aarhus University)

  • Jan Cools

    (VIB-KU Leuven)

  • Sean J. Morrison

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Jean-Christophe Marine

    (KU Leuven
    VIB Center for Cancer Biology)

  • Diether Lambrechts

    (VIB
    KU Leuven)

  • Massimiliano Mazzone

    (VIB
    KU Leuven
    University of Torino)

  • Gregory J. Hannon

    (University of Cambridge, Li Ka Shing Centre)

  • Sophia Y. Lunt

    (Michigan State University
    Michigan State University)

  • Thomas G. P. Grünewald

    (Institute of Pathology, Faculty of Medicine, LMU Munich
    Hopp Children’s Cancer Center (KiTZ)
    German Cancer Consortium (DKTK)
    Heidelberg University Hospital)

  • Morag Park

    (McGill University
    McGill University)

  • Jacco van Rheenen

    (Oncode Institute, The Netherlands Cancer Institute)

  • Sarah-Maria Fendt

    (VIB-KU Leuven Center for Cancer Biology, VIB
    KU Leuven and Leuven Cancer Institute (LKI))

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.

Suggested Citation

  • Matteo Rossi & Patricia Altea-Manzano & Margherita Demicco & Ginevra Doglioni & Laura Bornes & Marina Fukano & Anke Vandekeere & Alejandro M. Cuadros & Juan Fernández-García & Carla Riera-Domingo & Cr, 2022. "PHGDH heterogeneity potentiates cancer cell dissemination and metastasis," Nature, Nature, vol. 605(7911), pages 747-753, May.
  • Handle: RePEc:nat:nature:v:605:y:2022:i:7911:d:10.1038_s41586-022-04758-2
    DOI: 10.1038/s41586-022-04758-2
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    Citations

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    Cited by:

    1. Kui Wang & Li Luo & Shuyue Fu & Mao Wang & Zihao Wang & Lixia Dong & Xingyun Wu & Lunzhi Dai & Yong Peng & Guobo Shen & Hai-Ning Chen & Edouard Collins Nice & Xiawei Wei & Canhua Huang, 2023. "PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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