TGF-ß superfamily signalling in development and cancer

Lead Research Organisation: The Francis Crick Institute

Abstract

The research in my lab is focused on cell communication. We want to understand how one group of cells sends out chemical signals to adjacent populations of cells that change their behaviour, which can be anything from changing their growth rate, their shape, their ability to move, or their identity. This phenomenon, which we call cell signalling, is absolutely crucial for embryonic development, which is the process whereby a single cell (the fertilized egg) develops to eventually become a complex new born animal. Cell signalling is also a key process that goes awry in cancer. In this case, the chemical signals may be produced inappropriately, or alternatively, the cells may respond incorrectly, for instance, by carrying on growing when they are supposed to stop. The particular signals that we work on are essential for specifying different types of cells in the embryo and for shaping the embryo. They also play critical roles in driving both the development and spread of tumours in humans. We want to understand how this happens, so that we can eventually determine how to develop better drugs to treat different types of cancer.

Technical Summary

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

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.

Publications

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