Traditionally, the Oncogenetics section utilizes patient-derived cell models and their cDNA complemented counterparts as isogenic cell models to investigate hereditary cancer genes. As a next step, we are now using CRISPR/Cas-based gene editing to engineer tissue-specific cell models of clinically relevant mutations for functional classification and to study their effects on tumorigenesis in vitro. In addition, we created a genome-wide CRISPR screening pipeline in Cas9-inducible diploid human epithelial cells to screen isogenic models of cancer genes. The aim of this approach is to reveal molecular genetic networks which help us to pinpoint candidate biomarkers and druggable vulnerabilities. We are also performing genome-wide screens in combination with targeted cancer drugs to uncover the drug-sensitizing effects of gene inactivation and putative drug-resistance mechanisms. Building on our growing expertise in CRISPR technology, we are developing applications that allow the use of Cas12 in genome diagnostics. In the future, we hope to explore ways to implement targeted gene editing in therapeutically relevant clinical genetics.

Selected Publications

Van der Weegen Y, de Lint K, van den Heuvel D, Nakazawa Y, Mevissen TET, van Schie JJM, San Martin Alonso M, Boer DEC, Gonzalez-Prieto R, Narayanan IV, Klaassen NHM, Wondergem AP, Roohollahi K, Dorsman JC, Hara Y, Vertegaal ACO, de Lange J, Walter JC, Noordermeer SM, Ljungman M, Ogi T, Wolthuis RMF, Luijsterburg MS (2021) ELOF1 is a transcription-coupled DNA repair factor that directs RNA polymerase II ubiquitylation. Nat Cell Biol 23:595-607

Glykofridis IE, Knol JC, Balk JA, Westland D, Pham TV, Piersma SR, Lougheed SM, Derakhshan S, Veen P, Rooimans MA, van Mil SE, Bottger F, Poddighe PJ, van de Beek I, Drost J, Zwartkruis FJ, de Menezes RX, Meijers-Heijboer HE, Houweling AC, Jimenez CR, Wolthuis RM. (2021) Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells. Elife, 10:e61630

Van Schie, J.J., Faramarz, A., Balk, J.A., Stewart, G.S., Cantelli, E., Oostra, A.B., Rooimans, M.A., Parish, J.L., de Almeida Estéves, C., Dumic, K., Barisic, I., Diderich, K.E.M., van Slegtenhorst, M.A., Mahtab, M., Pisani, F.M., te Riele, H., Ameziane, N., Wolthuis, R.M.F., de Lange, J. (2020) Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion. Nat. Comm. 11:1-18.

Van Dongen, J.E., Berendsen, J.T., Steenbergen, R.D., Wolthuis, R.M.F., Eijkel, J.C., Segerink, L.I. (2020) Point-of-care CRISPR/Cas nucleic acid detection: Recent advances, challenges and opportunities. Biosensors and Bioelectronics 166:112445.

Van Harten AM, Buijze M, van der Mast R, Rooimans MA, Martens-de Kemp SR, Bachas C, Brink A, Stigter-van Walsum M, Wolthuis RMF, Brakenhoff RH (2019) Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death. Oncogenesis 8:38.

De Lange, J., Faramarz, A., Oostra, A.B., De Menezes, R.X., van der Meulen, I.H., Rooimans, M.A., Rockx, D.A., Brakenhoff, R.H., van Beusechem, V.W., King, R.W., Wolthuis, R.M.F. (2015) Defective sister chromatid cohesion is synthetically lethal with impaired APC/C function. Nat. Comm. 6:1-12.