Our research focuses primarily on the roles of signaling by transforming growth factors -a and -b (TGF-α and β) in epithelial and mesenchymal cell differentiation, as well as in carcinoma development and progression.
TGF-α is a growth factor for cell types from ectodermal origin, including most epithelial cells, and exerts its functions in an autocrine and paracrine fashion. TGF-α expression is often upregulated in carcinomas and TGF-α signaling through its receptor, the EGF/TGF-α receptors, is thought to drive carcinoma development. TGF-α is made as a transmembrane growth factor that can be proteolytically cleaved in a highly regulated manner and is then released. Little is as yet known about how the cell surface presentation of transmembrane TGF-α and its ectodomain cleavage are regulated.
Our TGF-α research focuses on the identification and functional characterization of proteins that form a complex in association with transmembrane TGF-α, and define the subcellular localization and presentation of transmembrane TGF-α. We study their functions in the presentation of transmembrane TGF-α, signaling and regulation of TGF-α ectodomain cleavage in normal and transformed epithelial cells. We also characterize signaling mechanisms that lead to ectodomain cleavage of transmembrane TGF-α, and consequent release of soluble TGF-α. Finally, we evaluate the consequences of these modes of regulation of TGF-α presentation on the cellular behavior and phenotype, and their role in the transition from normal epithelial cells to carcinomas.
TGF-β is a prototype for a large family of differentiation factors, the TGF-β family, that regulate development. TGF-β family signaling is of special relevance in cell differentiation. TGF-β induces epithelial-to-mesenchymal transition, which is an important process in normal development and fibrosis and initiates carcinoma invasion and metastasis. TGF-β family signaling also direct mesenchymal differentiation, e.g. in muscle, bone, cartilage and fat differentiation, and are important mediators in the maintenance of stem cell pluripotency and the engagement in and selection of differentiation pathways.
In one set of projects, we study how the Smads, a class of intracellular signaling effectors, regulate transcription activation and repression, and can influence epigenetic mechanisms of transcriptional (re)programming, as required in alterations in differentiation. Other studies focus on the discovery of new signaling pathways that emanate from the activated receptor complexes. These non-Smad signaling mechanisms are particularly relevant in the context of TGF-β’s ability to induce epithelial-to-mesenchymal differentiation.
Complementary projects study the roles of TGF-β/Smad signaling in mesenchymal differentiation, thereby focusing on muscle, fat and bone cell differentiation, and the underlying molecular mechanisms of this regulation. The characterization of the roles of TGF-β family signaling in cell differentiation, and of the signaling mechanisms, are the basis for our studies to explore the plasticity of the different mesenchymal differentiation pathways, both in cell culture and in engineered mouse models. These insights have recently allowed us to start exploring the role of TGF-β family signaling in the pluripotentiality and differentiation of embryonic stem cells.