TGF-SS AND CANCER · Role of TGF-B pathway in tumourigenesis

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Project objective

TGF-ss signalling pathways play an important role in embryonic development as well as intumouri genesis. TGF-ss signalling results in nuclear accumulation of active Smads complexes that regulate transcription of target genes. Alteration of certain TGF-ss pathway components is a frequent event in some human tumours such as colorectal or pancreatic tumours and mainly results from mutation or deletion of either the TGF-ss type II receptor or the Smad4 genes. More frequently however, human tumours tend to express lo w levels of either the type I or type II TGF-ss receptors.The mechanism by which the TGF-ss pathway contributes to tumour progression is unclear, but it is now known that it can act both as a tumour suppressor by inhibition of growth or as a tumour promoter by increasing motility and inducing epithelial to mesenchymal transition (EMT), invasiveness and metastasis. My project aims to understand how alteration of TGF-ss pathway components in tumours could explain how tumour cells become resistant to the growth in hibitory effects of TGF-ss, whilst maintaining responsiveness to the pro-oncogenic activities of TGF-ss. To assess this question, I will use inducible siRNA technology to generate human pancreatic cell lines that are specifically knocked-down for Smad4 or the type I TGF-ss receptor.The functional responsiveness of these cell lines to TGF-ss will be investigated by cell cycle analysis and migration assays and I will attempt to determine whether these cells have acquired a more aggressive phenotype by measuring their tumour igenicity. These results will be complemented with micro array analyses in order to determine which target genes are implicated in these different responses.Finally, using biochemical approaches in the inducible Smad4-siRNA pancreatic cell lines, I will seek to determine why the loss of Smad4 is particularly advantageous for pancreatic tumour progression.

Original text from CORDIS.

Participants

• CANCER RESEARCH UK · LONDONCoordinatorUnited Kingdom

Links

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