Deregulation of TGF-β family ligands in cancer

• Main Author: Bloxham, Robert David
• Format: Dissertation
• Language: English
• Published: UCL (University College London) 2021

The study of signalling dynamics is important for understanding how signalling pathways operate in health and disease. Previous work within the lab investigated how cells respond to TGF-β family ligands over time, in terms of pathway activity. Cells treated with TGF-β reach maximal signal induction at one hour which rapidly attenuates to a low-level steady state despite sustained ligand exposure. Additionally, cells become unresponsive to fresh ligand. This suggests that in diseases, including cancer, where there are sustained levels of pathway activity, another ligand may be responsible for signal propagation or there is re-wiring of mechanisms underlying TGF-β signalling dynamics. Further work in the lab demonstrated that reduced expression of components of the ESCRT machinery led to sustained pathway activity in cells exposed to TGF-β. Furthermore, it was shown that CAFs, a cell type in the tumour stroma, produce functional Activin ligand, which may also be responsible for sustained pathway activation. The work in this thesis aimed to investigate whether these two distinct possibilities could explain the sustained TGF-β family pathway activity observed in disease states by answering two questions: 1. Does compromised ESCRT signalling lead to enhanced TGF-β-mediated output? 2. Is CAF-sourced Activin responsible for pathway signal and output, previously ascribed to TGF-? I have demonstrated that compromised ESCRT function leads to an enhanced TGF-β-mediated epithelial-mesenchymal transition through elevated PSMAD signalling. I have also shown that CAFs from the MMTV-PyMT mouse model of breast cancer produce Activin, that is critical for their contractility whilst affecting their proteome and transcriptome. Furthermore, I have developed in vivo experiments to determine the role of CAF-sourced Activin during tumourigenesis.