Research themes
New diagnostics by genomic profiling
We will use various genomic approaches, including micro(RNA)array analysis, proteomics and chromosome conformation capture on chips, to obtain and validate genomic profiles associated with prognosis, therapy resistance or other relevant clinical endpoints such as the site of relapse. Validated profiles are of high clinical need to better characterize tumours, resulting in better prognosis and therapy. We will continue to build on the successful results obtained during the first phase of the CGC - i.e. 12 patented expression profiles for breast cancer – by validating existing profiles, developing new ones and expanding our efforts to other tumour types, such as lung cancer. We will use systems biology approaches to identify the oncogenic networks that are represented by these profiles to identify points of therapeutic interference. We will further investigate whether germline status of patients – also as determined by single nucleotide polymorphism analysis - is predictive for cancer risk and therapy response (Klijn/Foekens; Van’tVeer/Rodenhuis; Grosveld/Philipsen).
Novel therapeutic targets
In this theme we will use both mouse model systems and cell-based assays to identify such targets. In the mouse studies, we will induce tumours by insertional mutagenesis, allowing the rapid isolation of the genes affected. During the first phase of the CGC this method proved to be extreme successful for the identification of genes and combination of genes that are critical for the formation of leukaemia and has provided an unexpected wealth of information. Not only have large numbers of new oncogenes and tumour suppressor genes been marked, but also the co-mutations and the reciprocal exclusions that occur have provided additional information on the pathways that are involved in tumourigenesis. More than 600 potential oncogenes/tumor suppressor genes/microRNAs have been marked, which is considerably more than has been characterized to date worldwide using other techniques. During the second phase of the CGC, selected genes will be further validated as therapeutic targets. Furthermore, newly developed insertional mutagenesis protocols that specifically target selective tissues of mice will be used to induce breast and lung tumours, followed by the characterisation of genes that drive these tumours (Berns/Van Lohuizen; Grosveld). In the cell-based studies we will use genome-wide siRNA-mediated inhibition to identify genes that are particularly critical in tumours with specific oncogenic mutations. We thereby continue to build on investments made during the first phase of the CGC, which resulted in a large collection of 10,000 siRNA vectors that each suppresses the expression of a single gene, which makes it possible to perform large-scale screens in mammalian cells. These so-called “synthetic lethals” may be very sensitive therapeutic targets. In a different type of screen we will identify genes that confer resistance to therapy. These genes may be useful biomarkers, but also targets that can be exploited for drug resistant tumours, in particular in the context of new classes of targeted therapeutics such as Trastuzumab (Herceptin) (Bernards). During the first phase of the CGC, a large-scale RNA interference screen demonstrated that suppression of the tumour suppressor PTEN confers Trastuzumab resistance in breast cancer cell lines. We will expand on and further exploit these findings during the second phase of the CGC.
Molecular mechanisms of cancer
In this theme we study various aspects of the cancer process by a variety of genomic, biochemical and cell biological approaches as well as experiments at the level of intact organisms. We will study DNA repair processes and their role in the control of the integrity of the genome, which is invariably compromised in cancer. Particularly we will address the question how different mutations in repair/genome maintenance factors favour the development of cancers while others seem to confer protection and how those differences can be exploited either therapeutically or for cancer prevention (Hoeijmakers, Kanaar). C. elegans will be used to further identify genes involved in genome integrity. We will explore the mechanism by which microRNAs act and how they play a role in cancer as well as in developmental processes (Cuppen). To understand the mechanism of the formation of colon cancer we will study how stem cells in the gut are regulated to induce the various cell types and what goes wrong in this process when critical mutations cause cancer. A variety of genes have already been identified that are involved in this process. By a systematic genomics approach using expression arraying and ChIP-on-chip arraying we will unravel the transcriptional wiring of the crypt stem cell compartment and the alterations in the program in mouse and human adenoma and adenocarcinoma (Clevers). We will explore the signalling networks that control cell adhesion and cell migration - critical steps in cancer metastasis -, in order to find possible targets for intervention (Bos, Burgering). Finally we will analyse cell cycle control mechanisms to understand the mechanism of chemotoxic treatment, currently still one of the most common forms of cancer treatment (Medema). This third theme comprises the most basic research part of the CGC program and as such cannot be easily be pinpointed to predetermined goals relevant for clinical practice. However, we will be alert to (unexpected) findings of potential relevance for the clinic. For example, during the first phase of the CGC, an essential role was uncovered for Notch regarding the maintenance of crypt progenitors in the gut. Moreover, it was found that inhibition of Notch through pharmacological inhibition of gamma-secretase in adenomas induces terminal differentiation, indicating that gamma-secretase inhibitors may be useful to treat colon cancer. This result was the basis for the founding of the small biotech company Agamyxis by Clevers.