Van Boxtel Group
Ruben van Boxtel
The research of Ruben van Boxtel has been concentrated on studying genome stability in human health and disease. After obtaining his PhD, he joined the lab of Paul Coffer (UMC Utrecht) where he studied a transcriptional feedback mechanism of PI3K-AKT-FOXO signaling, which promotes survival of cancer cells upon anti-cancer treatment. In 2013, he moved to the group of Edwin Cuppen (Hubrecht Institute & UMC Utrecht) to determine genome stability of adult stem cells in organoid cultures. His research demonstrated that organoid cultures maintain remarkably high levels of genomic integrity. In 2015, he received a grant (TAS-ZonMW) to work as a visiting scientist in the group of Michael Stratton (Wellcome Trust Sanger Institute). In 2017, Ruben was appointed as a group leader at the Princess Máxima Center for pediatric oncology. In the same year, he received a NWO Vidi award to support his research focused on studying genomic integrity of human adult stem cells.
Our research team aims to study the molecular causes of childhood cancer and treatment-associated second malignancies. Our vision is that by understanding the processes that cause cancer, effective preventive therapies can be developed, diagnostics improved and choice of treatment facilitated. We focus on identifying mutational processes that drive cancer development across different tissues. To achieve our goals, we combine state-of-the-art stem cell culture technology, genomics and computational analyses. Using this unique approach, we have previously demonstrated that lifelong mutation accumulation in human stem cells can in part explain why certain organs display higher cancer incidence. Moreover, we have developed a strategy to explore the origin of cancer-associated mutational signatures by applying whole-genome sequencing to genetically modified human organoids using CRISPR/Cas9 technology.
To study the causes of childhood cancer, we will apply our approach to physiologically normal stem cells of individuals at risk for developing childhood cancer. By comparing the genome-wide mutation profiles of these cells with those observed in pediatric tumors, we can distinguish and characterize cancer-causing molecular processes. Similarly, by cataloguing the direct and indirect mutational consequences of chemotherapy, we will increase our understanding into the mechanisms by which anti-cancer treatment contributes to second malignancies. This work will facilitate the discovery of risk factors predictive for childhood cancer and therapy-associated second malignancies, and will contribute to improved clinical interpretation of whole-genome sequencing data.
• Jager M, Blokzijl F, Sasselli V, Boymans S, Janssen R, Besselink N, Clevers H, van Boxtel R*, Cuppen E*. Measuring mutation accumulation in single human adult stem cells by whole-genome sequencing of organoid cultures. Nature Protocols. 2017 in press
• Drost J*, van Boxtel R*, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, de Ligt J, Behjati S, Grolleman JE, van Wezel T, Nik-Zainal S, Kuiper RP, Cuppen E, Clevers H. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science. 2017 Oct 13;358(6360):234-238.
• Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S, Sasaki N, Huch M, Boymans S, Kuijk E, Prins P, Nijman IJ, Martincorena I, Mokry M, Wiegerinck CL, Middendorp S, Sato T, Schwank G, Nieuwenhuis EE, Verstegen MM, van der Laan LJ, de Jonge J, IJzermans JN, Vries RG, van de Wetering M, Stratton MR, Clevers H, Cuppen E, van Boxtel R. Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 2016 Oct 13;538(7624):260-264.
• Huch M*, Gehart H*, van Boxtel R*, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015 Jan 15;160(1-2):299-312.
• van Boxtel R, Gomez-Puerto C, Mokry M, Eijkelenboom A, van der Vos KE, Nieuwenhuis EE, Burgering BM, Lam EW, Coffer PJ. FOXP1 acts through a negative feedback loop to suppress FOXO-induced apoptosis. Cell Death Differ. 2013 Sep;20(9):1219-29.