title: The Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts.
abstract: Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential.
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Kuchnio
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Stijn
authors.initials: S
authors.lastname: Moens
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bruning
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Karol
authors.initials: K
authors.lastname: Kuchnio
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Cruys
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Broux
authors.affiliation: Laboratory of Soft Matter and Biophysics, Department of Physics and Astronomy, KU Leuven, Celestijnenlaan 200D, 3001 Heverlee, Belgium.
authors.forename: Andreea Alexandra
authors.initials: AA
authors.lastname: Ungureanu
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Leite de Oliveira
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bruyère
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Henar
authors.initials: H
authors.lastname: Cuervo
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Manderveld
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Carton
authors.affiliation: Laboratory of Vascular Proteomics, Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Juan Ramon
authors.initials: JR
authors.lastname: Hernandez-Fernaud
authors.affiliation: Laboratory of Vascular Proteomics, Cancer Research UK Beatson Institute, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Zanivan
authors.affiliation: Laboratory of Soft Matter and Biophysics, Department of Physics and Astronomy, KU Leuven, Celestijnenlaan 200D, 3001 Heverlee, Belgium; IMEC, Kapeldreef 75, 3001 Heverlee, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Bartic
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Avenue de l'Hôpital 3, 4000 Liège, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-Cancer, University of Liège, Avenue de l'Hôpital 3, 4000 Liège, Belgium.
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vinckier
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Herestraat 49, 3000 Leuven, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases