Control of the Wnt signaling outputs
A long-term goal of our research has been the dissection of the Wnt signaling pathway and the identification of the components involved. Our efforts have uncovered many key players, including Pangolin (Pan)/dTCF the transcription factor that transduces the Wg signal, as well as Legless (Lgs/Bcl-9) and Pygopus (Pygo), which both act as transcriptional cofactors. We have also found and characterized components critical for Wnt secretion, such as Wntless and the retromer complex.
As well as looking for new components we are working to delineate the signal transduction mechanism, with a focus on the translation of the signal into genetic program. Using state of the art techniques – RNA-Seq, ChIP-Seq, CRISPR – we are probing the Wnt response-ome during development, homeostasis and disease. For example, how specific Wnt outputs drive stem cell and tissue differentiation and how these outputs change during the development.
Our quest continues.
Wnt signaling and the stem cell niche
Tissue regeneration and homeostasis relies on stem cells. These are a self-replenishing pool of cells and serve as the source of the differentiated cells of tissues and organs. The stem cell niche is the surrounding microenvironment that orchestrates their fate. The interaction of stem cells with niche cells is coordinated by the involvement of different signaling pathways, including Wnt signaling. Deciphering the communication between the stem cell and its niche will impact our understanding of aging, regeneration, and diseases.
Focusing on epithelial stem cells in the gastrointestinal tract, specifically the colon, we are seeking to understand the role of Wnt ligands during homeostasis and regeneration. To do this we use genetically engineered mouse models and organoid-based approaches.
Wnt signaling in disease
Cancer is the scourge of modern society and our lab is involved in various translational research efforts to better understand how aberrant cell-cell communication leads to this disease.
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 are archetypal gatekeeper mutations; however the role of Wnt signaling in later stages of tumor progression is poorly understood. One research focus is to solve this mystery.
To do this we are working in close collaboration with various initiatives such as the URPP Translational Cancer Research. www.cancer.uzh.ch