Koen van de Wetering, PhD, DVM


Division of Molecular Oncology
The Netherlands Cancer Institute, Amsterdam, Netherlands


Koen van de Wetering (1972) studied Veterinary Medicine in Utrecht (DVM) and got his PhD for work on the lung surfactant system in the group of Bert van Golde. In 2003 Koen joined the Multidrug Resistance (MDR) group of Piet Borst at the Netherlands Cancer Institute and initially focused on the pharmacological roles of ABCC3 (MRP3). The last couple of years he has set up methods employing metabolomics to search for the physiological substrates of the ABCCs (MRPs). Using this metabolic approach several new substrates of ABCC2 (MRP2), ABCC3 (MRP3) and ABCG2 (BCRP) have been identified. Recently it has become clear that PXE is a metabolic disease caused by the absence of a factor in blood normally provided by ABCC6 (MRP6) from the liver. Our group has used metabolic approaches to identify the compounds that are specifically released by cells expressing ABCC6. Interestingly, we found that ABCC6 mediates the release of ATP from cells. Extracellularly, released ATP is converted into AMP and pyrophosphate (PPi), a major inhibitor of ectopic mineralization. Our work also showed that in PXE patients, lack of ABCC6-mediated ATP release results in severely reduced PPi levels in the blood. These low PPi levels explain the ectopic mineralization phenotype in PXE patients. We are now focusing on the development of treatment strategies for PXE that are aimed at normalizing plasma PPi levels.

Interview with Dr. van de Wetering 
Webinar "Searching for the ABCC6 Substrate"
Webinar "ABCC6 prevents the ectopic mineralization seen in PXE by mediating hepatic ATP release"
 


Areas of Interest


Assay Development
PXE and the Metabolism
 


Publications


Jansen RS, Duijst S, Mahakena S, Sommer D, Szeri F, Váradi A, Plomp A, Bergen AA, Oude Elferink RP, Borst P,van de Wetering K. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1985-9. Lay summary. PMID: 24969777

Jansen RS, Küçükosmanoğlu A, de Haas M, Sapthu S, Otero JA, Hegman IE, Bergen AA, Gorgels TG, Borst P,van de Wetering K. ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20206-11. Free article in PubMed. Lay summary. PMID: 24277820

Krumpochova P, Sapthu S, Brouwers JF, de Haas M, de Vos R, Borst P, van de Wetering K. Transportomics: screening for substrates of ABC transporters in body fluids using vesicular transport assays.FASEB J. 2012 Feb;26(2):738-47. Free article at Journal Website. PMID: 22034653

Fülöp K, Jiang Q, van de Wetering K, Pomozi V, Szabó PT, Arányi T, Sarkadi B, Borst P, Uitto J, Váradi A. ABCC6 does not transport vitamin K3-glutathione conjugate from the liver: Relevance to pathomechanisms of pseudoxanthoma elasticum. Biochem Biophys Res Commun. 2011 Nov 25;415(3):468-71. Free article in PubMed. PMID: 22056557

Borst P, van de Wetering K, Schlingemann R. Does the absence of ABCC6 (Multidrug Resistance Protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery? Cell Cycle. 2008 Jun 1; 7(11):1575-9. Free article at Journal Website. PMID: 18469514