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

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

PMID: 35585241   DOI: 10.1038/s41586-022-04758-2

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 process^2,3. 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 Phgdh^low 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 α_vβ₃, which potentiates cell migration and invasion. Inhibition of sialylation counteracts the metastatic ability of Phgdh^low 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.