I started my independent immunology lab in Utrecht in 1989. Our primary research interest involved the identification of novel T lymphocyte transcription factors. We soon cloned the founding member of a novel transcription factor family, T Cell Factor (TCF)-1 as well as multiple vertebrate and invertebrate TCFs. Birchmeier and we independently determined that TCFs constitute the effectors of the Wnt/β-catenin pathway (published by us as Molenaar et al., Cell 1996 and van de Wetering et al., Cell 1997).
We proposed a molecular mechanism by demonstrating that β-catenin acts as a transcriptional co-activator for TCF and developed the widely used pTOPFlash Wnt reporter assay. In 1997, we proposed that the constitutive formation of β-catenin/Tcf4 complexes in the nuclei of APC-mutant represents the principle transforming event in colon cancer, a finding published in collaboration with the Vogelstein lab (Korinek et al., Science 1997 and Morin et al. Science 1997). This finding was followed in 1998 by our demonstration that Tcf4 mutant mice fail to establish stem cell compartments in intestinal crypts (Korinek et al, Nature Genetics 1998), the first link between Wnt signaling and mammalian stem cells. In these and subsequent studies, we introduced a variety of model organisms into the lab, including Xenopus, Drosophila, C. elegans and Danio rerio, thus familiarizing ourselves with developmental biology concepts. Thus, driven by these results, my interests gradually moved away from immunology to developmental biology, and then to cancer and stem cell biology.
Over the past ten years, we have shifted our focus from non-mammalian organisms to the role of developmental signaling pathways in stem cells in the adult intestine and other internal organs in health and disease. We typically address questions first by generating large datasets (for instance by microarraying), followed by the construction of genetic mouse models in candidate gene approaches, after which we attempt to apply novel insights to man. We have pioneered the self-renewing mammalian intestinal epithelium as a model system for the study of adult stem cell biology and cancer. This has culminated in the definitive identification of the intestinal stem cell through the novel Lgr5 marker (Barker et al, Nature 2007) and the development of in vitro long-term culture methods for self-organizing epithelial organoids in mouse and man (Sato et al, Nature 2009/2011). Based on these observations, we have identified a range of adult stem cells in mouse and man (a.o. for hair follicle, prostate, liver, pancreas, stomach) and developed culture methods for these adult organ stem cells. We have also developed a toolbox for genetic modification, and molecular/biochemical/imaging analyses of these organoids.
Based on these observations, we have identified a range of adult epithelial stem cells in mouse and man (a.o. for hair follicle, prostate, liver, pancreas, stomach) and developed culture methods for these adult organ stem cells and the carcinomas derived thereof. We have also developed a toolbox for genetic modification, and molecular/biochemical/imaging analyses of these organoids (e.g. Drost et al, Nature 2015).