Signaling in Development and Disease

An overarching theme of our research is the dissection of the signaling pathways that control development and are dysregulated in disease. More specifically we want to delineate the signal transduction mechanisms of those pathways and to characterize the activated genetic programs. We do this in different biological contexts and model organisms.

One mainstay of our work has been characterization of the Wnt pathway. Our work has uncovered key pathway components and elucidated many of the underlying molecular mechanisms. Dysregulated Wnt signaling is implicated in the etiology of many cancer types. A prominent case is colorectal cancer in which mutations that activate Wnt signaling act as archetypal gatekeeper mutations. The role of Wnt signaling in later stages of tumor progression is poorly understood. We are working to solve this mystery.
A newer topic we are exploring is how reactivation of embryonic genetic programs drives tissue regeneration and disease progression. In acute conditions, reactivated embryonic programs repair the damage and allow a return to homeostasis. In chronic situations, such as inflammatory diseases, fibrosis and cancer, prolonged activation of embryonic programs leads to disease progression and tissue deterioration.
For our exploration, we use state of the art techniques – single cell RNA-Seq, ChIP-Seq, CRISPR – to probe the underlying regulatory mechanisms, as well as cellular fate. We use mouse models as experimental systems to mimic different biological contexts and ex vivo models to perform fast and reliable functional analyses. To assess evolutionary conservation and clinical translatability, we also use patient material obtained via a collaboration with University Hospital Zurich.

Wnts are a conserved family of signaling molecules that play pivotal roles in development and disease. Different types of Wnt signaling – β-catenin dependent (i.e., canonical) and independent (non-canonical) – elicit different responses and fulfill different roles. Compared with Wingless (Wg), little is known about the roles played by the six other Wnts encoded in the Drosophila genome. Using the Drosophila digestive tract as a model system, we areo characterizing the role and function of these Wnts during development, homeostasis, and regeneration.
To define the roles of Wnts in the adult Drosophila intestine we are exploring their expression during homeostasis and in perturbed conditions. Using conditional loss- and gain-of function approaches, as well as Wnt ORF swapping, we are revealing the flavor of the elicited signals and exploring the potential for functional redundancy. The results will allow us to better understand Wnt function and may provide insights into the roles of Wnts in other organisms.