Title: TGF-β superfamily signalling in development and cancer
Funder: The Francis Crick Institute

Abstract: The fundamental biological problem I want to solve is how do extracellular signals, in the context of whole organisms, regulate new programmes of gene expression in receiving cells and thus determine cell behaviour, which underpins normal embryonic development and human pathologies. To do this we have been focusing on the transforming growth factor b (TGF-b) family of growth and differentiation factors, which include the TGF-bs, Activins, Nodals, BMPs and GDFs. Many of these ligands play fundamental roles in early vertebrate development, acting as morphogens in the specification and patterning of the germ layers, and are essential in adult organisms for tissue homeostasis and stem cell function. Malfunction of signalling downstream of TGF-b, BMPs and Nodal causes serious human diseases such as cancer, fibrosis, wound healing disorders and also several hereditary conditions such as familial primary pulmonary hypertension, marfan syndrome, fibrodysplasia ossificans progressiva and hereditary hemorrhagic telangiectasia. Understanding how these signalling pathways function both at the mechanistic level and in vivo promises to provide significant insights into the biological processes they control and into human diseases, and also has the potential to lead to new therapeutics. A major goal of my lab is to understand at the molecular level how these ligands signal from the plasma membrane to the nucleus and how they regulate transcription of target genes. We want to determine how they function and are regulated in embryonic development, using zebrafish as a model system, and how these signalling pathways are hijacked by tumour cells to both promote growth of primary tumours and metastasis to distant sites. To achieve these goals my lab takes an unusually broad but extremely powerful approach, combining in vitro mechanistic investigation and computational modelling with in vivo analysis in early vertebrate embryos and in mouse tumour models. Current projects in my lab are focused on all of these areas. Concerning the mechanism whereby signalling by these ligands regulates transcription, we have recently delineated the sequence of events that occur from the binding of activated Smad2 (the intracellular transducer of these signals) to chromatin to regulation of gene expression. We have been focusing on signalling dynamics of these ligands and have shown that they are distinct for different ligands, and high throughput siRNA screens have uncovered new components responsible for determining the signalling dynamics. We have discovered a new pathway downstream of TGF-b and determined the underlying mechanism and its function. The data suggest that it may be crucial for the tumour-promoting activities of TGF-b. In early zebrafish embryos we have demonstrated how interplay between Nodal and FGF signalling leads to endoderm specification. Finally, other projects in the lab are focused on the role of BMP signalling in the specification of the telencephalon in zebrafish, and how mutations in the Smad2/3-interaction domain of the transcriptional repressor, SKI, lead to Shprintzen-Goldberg syndrome, which is a Marfan-related disorder.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS