1. Academic Validation
  2. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

PHGDH heterogeneity potentiates cancer cell dissemination and metastasis

  • Nature. 2022 May;605(7911):747-753. doi: 10.1038/s41586-022-04758-2.
Matteo Rossi  # 1 2 Patricia Altea-Manzano  # 1 2 Margherita Demicco 1 2 Ginevra Doglioni 1 2 Laura Bornes 3 Marina Fukano 4 5 6 Anke Vandekeere 1 2 Alejandro M Cuadros 1 2 Juan Fernández-García 1 2 Carla Riera-Domingo 7 8 Cristina Jauset 9 Mélanie Planque 1 2 H Furkan Alkan 1 2 David Nittner 10 11 Dongmei Zuo 6 Lindsay A Broadfield 1 2 Sweta Parik 1 2 Antonino Alejandro Pane 1 2 Francesca Rizzollo 1 2 Gianmarco Rinaldi 1 2 Tao Zhang 12 Shao Thing Teoh 13 Arin B Aurora 14 Panagiotis Karras 11 15 Ines Vermeire 1 2 Dorien Broekaert 1 2 Joke Van Elsen 1 2 Maximilian M L Knott 16 Martin F Orth 16 Sofie Demeyer 17 Guy Eelen 18 19 Lacey E Dobrolecki 20 Ayse Bassez 21 22 Thomas Van Brussel 21 22 Karl Sotlar 23 Michael T Lewis 20 Harald Bartsch 24 Manfred Wuhrer 12 Peter van Veelen 12 Peter Carmeliet 18 19 25 26 Jan Cools 17 Sean J Morrison 14 27 Jean-Christophe Marine 11 15 Diether Lambrechts 21 22 Massimiliano Mazzone 7 8 28 Gregory J Hannon 9 Sophia Y Lunt 13 29 Thomas G P Grünewald 16 30 31 32 Morag Park 5 6 Jacco van Rheenen 3 Sarah-Maria Fendt 33 34
Affiliations

Affiliations

  • 1 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
  • 2 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 3 Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 4 Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, Quebec, Canada.
  • 5 Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada.
  • 6 Rosalind & Morris Goodman Cancer Institute (GCI), McGill University, Montreal, Quebec, Canada.
  • 7 Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium.
  • 8 Laboratory of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 9 Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK.
  • 10 Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
  • 11 Department of Oncology, KU Leuven, Leuven, Belgium.
  • 12 Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
  • 13 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA.
  • 14 Children's Research Institute and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 15 Laboratory of Molecular Cancer Biology, VIB Center for Cancer Biology, Leuven, Belgium.
  • 16 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • 17 Laboratory for Molecular Biology of Leukemia, VIB-KU Leuven, Leuven, Belgium.
  • 18 Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 19 Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium.
  • 20 StemMed, Houston, TX, USA.
  • 21 Laboratory for Translational Genetics, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
  • 22 Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 23 Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
  • 24 Institute of Pathology, Ludwig Maximilians University, Munich, Germany.
  • 25 Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates.
  • 26 Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 27 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 28 Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Centre, University of Torino, Torino, Italy.
  • 29 Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, MI, USA.
  • 30 Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • 31 Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 32 Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 33 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium. [email protected].
  • 34 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. [email protected].
  • # Contributed equally.
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.

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