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Tumor Biology & Immunology: Hein te Riele


Hein te Riele Ph.D. professorGroup Leader

About Hein te Riele

Research interests
Genetic defects in DNA mismatch repair (MMR) underlie the cancer syndrome hereditary non-polyposis colorectal cancer (HNPCC), nowadays known as Lynch syndrome (LS). MMR corrects DNA replication errors but also counteracts homologous recombination between slightly diverged DNA sequences. Furthermore, MMR mediates cell killing and suppresses mutagenesis by methylating agents. Mismatches in DNA are recognized by MSH2/MSH6 or MSH2/MSH3 heterodimeric protein complexes. Subsequent recruitment of another dimer, MLH1/PMS2, activates exonucleolytic activity to remove the error-containing DNA strand. Resynthesis of a new error-free strand completes the repair process. By fully disrupting MMR genes or substituting single codons in mouse embryonic stem cells (ESC) and mice, we investigate which of the MMR functions is critical to suppression of tumorigenesis.

A new mouse model for Lynch syndrome
Most recently, we have generated a new mouse model, in which MSH2-deficient cells arise in the intestine amidst a vast excess of MSH2-proficient cells, thus mimicking the situation in LS patients. These animals spontaneously develop intestinal tumors after approximately 18 months. We are using these mice to study whether tumor development (1) can be modulated by dietary factors or pharmacological intervention, and (2) is subject to immunosurveillance.

Characterization of unclassified MMR gene variants
Single codon variants of MMR genes are widespread in the human population and in (suspected) LS patients but their phenotypic consequences are often difficult to predict. To assess the pathogenicity of such 'Variants of uncertain significance' (VUS), we have developed a three-step approach: (1) Oligonucleotide-directed gene targeting is used to recreate the variant allele in the endogenous MMR gene in mouse ESCs. (2) Targeted cells are rendered hemizygous for the mutation, e.g., by disrupting the wild-type allele by conventional gene targeting, generating Msh2mut/- ESC lines. (3) The capacity of the variant allele to support MMR functions is assessed by measuring the level of mutant protein and by using assays for mutation avoidance, anti-recombination and DNA damage response (Wielders et al., 2011).

We expect our approach to allow unambiguous classification of VUS as polymorphic or pathogenic, thus helping clinical geneticists in counseling of mutation carriers. Our approach will be extended to other MMR genes and may also be applied to VUS of genes involved in other cancer syndromes like hereditary breast and ovarian cancer or Li-Fraumeni syndrome.

Oligonucleotide-directed gene modification
To insert or substitute one or a few base pairs at a desired location in the ESC genome, we have developed a novel technique that makes use of sequence-specific single-stranded oligodeoxyribonucleotides (ssODN) of ±35 residues (Dekker et al., 2003; 2006). However, "oligo targeting" is severely hampered by DNA mismatch repair activity and therefore we need to transiently disable the MMR machinery by RNA interference (Aarts et al., 2006; Dekker et al., 2011). Most recently, we found alternative ways to evade MMR, greatly expanding the applicability of oligo targeting. Furthermore, by studying the mechanism of oligo targeting, we expect to gain insight in the molecular details of the MMR reaction.

Fanconi anemia (FA) is a recessive hereditary disease characterized by developmental malformations, progressive anemia and cancer predisposition. At the cellular level, loss of any of the 15 genes that have been implicated in FA leads to cell killing and chromosomal aberrations by DNA crosslinking agents. In collaboration with the group of Johan de Winter at the VU University Medical Center Amsterdam, we are studying the consequences of genetic defects in the FA pathway for the etiology and behavior of tumors (Bakker et al., 2009; 2012; 2013).

Loss of G1/S control is a frequent if not mandatory event in tumor development. G1/S control relies on the retinoblastoma protein family pRB, p107 and p130 (pocket proteins), which collectively regulate the activity of E2F transcription factors. In the past, we have generated ESC lines carrying single and compound disruptions in the retinoblastoma genes (Rb-/-; Rb-/-p107-/-; Rb-/-p130-/-; Rb-/-p107-/-p130-/-). We have used these cells to generate chimeric mice and found that retinoblastoma development in mice required concomitant loss of Rb and p107 or Rb and p130. Furthermore, we have derived DKO and TKO mouse embryonic fibroblasts (MEFs) to study residual cell cycle control mechanisms and to identify events that promote oncogenic transformation.

Growth factor independence
While full ablation of the retinoblastoma gene family abrogates the G1-S checkpoint in MEFs, this is not sufficient for unrestricted proliferation. E.g., mitogen-deprived TKO MEFs can normally enter S-phase but then undergo apoptosis or arrest with a G2-like DNA content (Foijer et al., 2005). This G2 arrest is accompanied by severe DNA damage and cohesion defects (Van Harn et al., 2010). We are currently investigating the origin of DNA damage and the mechanism of G2 arrest, its involvement in restricting proliferation under a number of growth-inhibiting conditions and its significance as a suppressor or promoter of oncogenic transformation in vivo.

Anchorage independence
Although DKO and TKO MEFs are immortal and refractory to RASV12-induced senescence, RASV12-expressing DKO and TKO MEFs were unable to grow anchorage-independently and did not form tumors in nude mice. Apparently, a cell cycle mechanism still operates to restrict proliferation of TKO cells in the absence of anchorage. To identify this mechanism, we have used both gain- and loss-of-function screening.

In a gain-of-function screen in RASV12-Rb-/-p130-/- MEFs we identified the immortalizing oncogene TBX2 to confer anchorage-independent growth (Vormer et al., 2008). The growth-promoting activity of TBX2 in anchor-deprived DKO/TKO cells could be attributed to decreased association of p21CIP1 with Cyclin B1 and CDK2 and increased CDK1/2 activity.
To obtain further insight into the mechanism of transformation by TBX2, we performed a loss-of-function screen. For loss-of-function screening, we have developed a method that allows enzymatic production of low complexity shRNA libraries, i.e., libraries targeting primarily regulated genes that likely act as tumor suppressors. We identified 75 suppressor transcripts of which 33 appeared to act in a signaling network including p53, p21 and the mitogen-activated protein kinases Erk and p38. This suggests that TBX2 transforms cells by changing the balance between RASV12-mediated pro-mitotic ERK signaling and anti-mitotic p38-mediated stress signaling. We could demonstrate that p21 induction in anchor-deprived non-transformed cells resulted from p38-MK3-mediated stress signaling, which was relieved by ectopic expression of TBX2. Furthermore, we identified fournon-codingsuppressor transcripts demonstrating that our approach is capable of identifying non-coding suppressors of oncogenic transformation (Wielders et al., manuscript submitted).



Marleen Dekker-Vlaar

Research technician


I studied biochemistry at the HLO in Beverwijk. In 1990, after a studentship in the group of Peter Demant, I started working in the group of Anton Berns. In 1994 I joined the new research group of Hein te Riele where I have been working on different projects. I started on the retinoblastoma protein family project by generating ESC lines disrupting the retinoblastoma genes. Later I contributed to the DNA MMR project by generating and analyzing ESC lines and mouse models. Oligonucleotide-directed gene modification is one of the latest projects to which I contributed.

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Boogaard, Chantal

Chantal Bogaard-Stoepker, PhD

Postdoctoral Fellow


I completed a MSc in Oncology, followed by a PhD at the VU University Medical Center, where I worked on the cancer predisposition syndrome Fanconi anemia (FA). We identified mutations in SLX4 as causative for a subtype of FA and I investigated the FA DNA repair pathway in sporadic head and neck cancer. As a postdoctoral fellow at the Leiden University Medical Center, I continued working in the field of DNA repair. Now at the NKI, my project aims to improve and help implement a diagnostic test to classify disease-causing mutations in Lynch syndrome, a form of hereditary colorectal cancer.

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Benedict, Bente

Bente Benedict

Ph.D. Student


Loss of the G1/S phase checkpoint can cause severe replication stress and DNA damage, activating the DNA damage response pathway. Full-blown tumor growth requires alleviation of this pathway. My project aims to study the implications of this phenomenon for tumor development and therapeutic intervention.

Prior to joining the Te Riele group at the NKI, I completed a BSc in Biomedical Sciences and my MSc in
Molecular Mechanisms of Disease at the Radboud University Nijmegen.


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Frank van Gemert

Ph.D. Student


I studied Biomedical Sciences followed by a research master in Oncology at the VU University. For my final practical training I worked in the lab of Fred van Leeuwen at the NKI. Afterwards I joined the Hein te Riele lab where I now study DNA replication stress in cancer. It is my ambition to identify dependencies of cells suffering from replication stress. Since DNA replication is perturbed in cancer cells specifically, targeting such vulnerabilities may have therapeutic value. I aim to identify these vulnerabilities in vitro and test their potential to halt tumor growth in vivo.

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Pieters, Wietske

Wietske Pieters

Ph.D. Student


My project aims at the development of prevention strategies for intestinal cancer in Lynch syndrome (LS). With the use of mouse models, I focus on distinct factors that may influence the pathogenesis of colorectal cancer in LS patients, and investigate whether preventive measures can be taken to reduce tumor incidence and improve treatment options in this patient group.

Before starting my PhD in August 2015, I obtained my BSc in Biomedical Sciences and
MSc in Oncology at the VU university in Amsterdam.

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Ravesteyn, Thomas van

Thomas van Ravesteyn

Ph.D. Student


In September 2013 I joined the lab of Hein te Riele to study and improve oligonucleotide-directed subtle gene modification. I will evaluate the role of DNA mismatch repair in suppressing this technology in order to increase it's efficacy and applicability.

Previously, I acquired my MSc. at Utrecht University in the 'Cancer Genomics and Developmental Biology'-programme. As a component of my studies I worked in the lab of Torsten Witmman (UCSF) on microtubule cytoskeleton and in the lab of prof. dr. W. de Laat (Hubrecht Institute) on spatial chromatin organization.

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Research updates View All Updates

  • Improved oligonucleotide-directed gene modification

    We recently found that mismatches in DNA arising during oligonucleotide-directed gene modification can be made invisible for the MMR system allowing effective oligo targeting in MMR-proficient cells.

Key publications View All Publications

  • Loss of Rb proteins causes genomic instability in the absence of mitogenic signaling

    Genes Dev. 2010; 24: 1377-88.

    Van Harn T, Foijer F, van Vugt M, Banerjee R, Yang F, Oostra A, Joenje H, Te Riele H.

    link to PubMed

Recent publications View All Publications

  • Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation Associated with Gallbladder Carcinoma

    Cell Host Microbe. 2015 Jun 10;17(6):763-74

    Scanu T, Spaapen RM, Bakker JM, Pratap CB, Wu LE2 Hofland I, Broeks A, Shukla VK, Kumar M, Janssen H, Song JY, Neefjes-Borst EA, Te Riele H, Holden DW, Nath G, Neefjes J

    link to PubMed
  • DNA helicases FANCM and DDX11 are determinants of PARP inhibitor sensitivity

    DNA Repair (Amst). 2015 Feb;26:54-64

    Stoepker C, Faramarz A, Rooimans MA, van Mil SE, Balk JA, Velleuer E, Ameziane N, Te Riele H, de Winter JP

    link te PubMed


  • Office manager

    Karin van der Heijden

  • E-mail

  • Telephone Number

    +31 20 512 2055


'Research for the benefit of cancer patients'

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