Voorhoeve, Mathijs

Research Interests:

I am interested in the interaction between genetic events that change primary cells into tumour cells, and I aim to elucidate these using an in vitro model for transformation of human cells.

The lab of Molecular Tumor Genetics is expanding the in vitro transformation model using more cancer-relevant cell types such as epithelial cells and optimizing and sensitizing these cells for the transformation assay. Using these tools we are systematically investigating the oncogenic potential of microRNAs found to be over-expressed in cancer and characterizing the tumour suppressor pathways inhibited by these miRNAs.

The identification of targets relevant to the transforming phenotype caused by overexpression of oncogenic miRNAs is one of the major questions in the field. We address this by functionally testing the consequence of shRNA-mediated inhibition of the microRNA targets, individually or in combinations. This should deepen the understanding of cancer-associated miRNAs and their consequences for the tumour phenotype, and uncover tumor suppressors whose inactivation synergistically contributes to oncogenic transformation.

This system can also contribute to the characterization of other growth-regulating and/or cancer-associated genetic elements by allowing the mapping of the affected genetic pathways, and providing an accessible system for a first biochemical analysis. In a collaboration with Dr. A.M. Pietersen we are isolating novel microRNAs whose expression is restricted to mammary stem cells and may play a role in the prevention of differentiation or the maintenance of proliferative capacity, two traits very relevant to tumorigenesis. Moreover we are testing a new class of noncoding RNAs that have recently been shown to be differentially expressed in cancers for their transforming or tumor-suppressive potential in this model, to begin to understand their mode of action.

Selected Publications:

Voorhoeve PM. microRNAs: Oncogenes, Tumor Suppressors, or Master Regulators of Cancer Heterogeneity?
BBA Reviews in Cancer. 2009 Sept. Review.

Haupt S, di Agostino S, Mizrahi I, Alsheich-Bartok O, Voorhoeve PM, Damalas A, Blandino G, Haupt Y
PML is required for gain of function by mutant p53.
Cancer Research 2009 vol. 69 (11) pp. 4818-26

Kedde M, Strasser MJ, Boldajipour B, Oude Vrielink JAF, Slanchev K, le Sage C, Nagel R, Voorhoeve PM, van Duijse J, Ørom U, Lund A, Perrakis A, Raz E, Agami RRNA-Binding Protein Dnd1 Inhibits MicroRNA Access to Target mRNA Cell. 2007 Dec 28;131(7):1273-86.

Voorhoeve PM#, Agami R#.Classifying microRNAs in cancer: the Good, the Bad, and the Ugly.BBA Reviews in Cancer. 2007 Jun;1775(2):274-82. Review. #corresponding authors

Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R.A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006 Mar 24;124(6):1169-81.

Kolfschoten IG, van Leeuwen B, Berns K, Mullenders J, Beijersbergen RL, Bernards R, Voorhoeve PM, Agami R.A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity.Cell. 2005 Jun 17;121(6):849-58.

Voorhoeve PM, Agami R.Unraveling human tumor suppressor pathways: a tale of the INK4A locus.Cell Cycle. 2004 May;3(5):616-20. Review.

Voorhoeve PM, Agami R.The tumor suppressive functions of the human INK4A locus.Cancer Cell, 2003 October 4;(4), 311-319

Voorhoeve PM, Agami R.Knockdown stands up.Trends Biotechnol. 2003 Jan;21(1):2-4. Review.

Voorhoeve PM, Watson RJ, Farlie PG, Bernards R, Lam EW.Rapid dephosphorylation of p107 following UV irradiation.Oncogene. 1999 Jan 21;18(3):679-88.