Our group studies cell signaling in intestinal stem cells and colorectal cancer (CRC), which is the third leading cause of death from cancer among adults. As a model for the healthy and transformed epithelium we use stem cell-derived ‘organoids’: This 3D culture system allows formation of epithelial structures that undergo continuous self-renewal and differentiation, recapitulating the normal crypt-villus architecture of the gut (see Sato et. al., Nature 2009). Organoid cultures offer the unique opportunity to study epithelial contributions in complex pathologies such as cancer. The possibility to expand and characterize primary cells from endoscopic biopsies allows to generate patient-specific models. Accessibility to transgenesis technologies such as CRISPR/Cas9 and lentiviral overexpression provides us with a powerful genetic model.
Exogenous signals from multiple sources such as epithelial cells and surrounding mesenchyme confine stem cells and proliferation to the crypt. One unique feature of the organoid system is the presence of a stable stem cell compartment: At the bottom of the crypt-like protrusions dedicated niche cells the so-called Paneth cells produce Wnt3 and thereby locally instruct a stem cell fate. We study the molecular and cellular mechanisms how stem cell signaling and differentiation is organized. Co-culture with non-epithelial cells is performed to address influences from the surrounding tissues.
A heterogeneous spectrum of oncogenic driver mutations has been identified in CRC. Unfortunately we cannot predict phenotypes and therapeutic responses based on genetic data. This is due to the complexity of cell signaling processes that involve an intrinsic crosstalk between all tissue compartments. Oncogenesis reflects an evolutional co-adaptation to the tumor microenvironment: the tumor microenvironment critically influences progression but solid cancers also actively recruit stromal cells such as vasculature and fibroblasts to obtain trophic signals and actively repress immune responses. Disseminated tumor cells need to re-establish a supportive stroma to survive at secondary sites.
Current models such as (CRC)-cell lines have lost important traits of primary tumors and cannot reflect the heterogenic nature of the disease. In contrast, organoids remain dependent on exogenous niche signals that are supplemented with the growth medium. Importantly, these factors represent the same pathways that are most frequently dysregulated in CRC including Wnt, BMP, Tgfb, RTK/Ras, offering a physiologic model to analyze these signaling processes. Exposure to microenvironmental signals such as inflammatory cytokines, growth factors, microbial and metabolic cues are studied to identify tumor-specific vulnerabilities. More complex models such transgenic mice and transplantations are used to validate our hypotheses in vivo.
The project is funded by the German Consortium for Translational Cancer Research (DKTK) which is part of the German Cancer Research Centre (DKFZ).
The group encourages applications for MSs or PhD theses and we are happy to host internships for motivated students. Candidates should apply contact Farin@gsh.uni-frankfurt.de.