29 April 2012

Gene against pancreatic cancer discovered

Study points to potential new treatment for deadly pancreatic cancer

Transposon-mediated insertional mutagenesis accelerates the progression of ductal pancreatic cancer in mice.

Transposon-mediated insertional mutagenesis accelerates the progression of ductal pancreatic cancer in mice.

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In a study published in Nature today (Sunday 29 April), researchers have identified a potential new therapeutic target for pancreatic cancer.

The team found that when a gene involved in protein degradation is switched-off through chemical tags on the DNA's surface, pancreatic cancer cells are protected from the bodies' natural cell death processes, become more aggressive, and can rapidly spread.

Pancreatic cancer kills around 8,000 people every year in the UK and, although survival rates are gradually improving, fewer than 1 in 5 patients survive for a year or more following their diagnosis.

Co-lead author Professor David Tuveson, from Cancer Research UK's Cambridge Research Institute, said: "The genetics of pancreatic cancer has already been studied in some detail, so we were surprised to find that this gene hadn't been picked up before. We suspected that the fault wasn't in the genetic code at all, but in the chemical tags on the surface of the DNA that switch genes on and off, and by running more lab tests we were able to confirm this."

The team expects this gene, USP9X, could be faulty in up to 15 per cent of pancreatic cancers, raising the prospect that existing drugs, which strip away these chemical tags, could be an effective way of treating some pancreatic cancers.

" This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer. "

Dr David Adams

"Drugs which strip away these tags are already showing promise in lung cancer and this study suggests they could also be effective in treating up to 15 per cent of pancreatic cancers," continues Professor Tuveson.

The researchers used a mouse model of pancreatic cancer to screen for genes that speed up pancreatic cancer growth using a technique called 'Sleeping Beauty transposon mutagenesis'. This system uses mobile genetic elements that hop around the cell's DNA from one location to the next. Cells that acquire mutations in genes that contribute to cancer development will grow out and 'driver' cancer genes may be identified.

By introducing the Sleeping Beauty transposon into mice pre-disposed to develop pancreatic cancer, the researchers were able to screen for a class of genes called a tumour suppressor that, under normal circumstances, would protect against cancer. These genes are a bit like the cell's 'brakes', so when they become faulty there is little to stop the cell from multiplying out of control.

This approach uncovered many genes already linked to pancreatic cancer. But unexpectedly, USP9X, was identified.

Co-lead author Dr David Adams, from the Wellcome Trust Sanger Institute, said: "The human genome sequence has delivered many promising new leads and transformed our understanding of cancer. Without it, we would have only a small, shattered glimpse into the causes of this disease. This study strengthens our emerging understanding that we must also look into the biology of cells to identify all the genes that play a role in cancer."

Notes to Editors

Publication details

  • The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

    Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL, Silverstein KA, Grützmann R, Aust D, Rümmele P, Knösel T, Herd C, Stemple DL, Kettleborough R, Brosnan JA, Li A, Morgan R, Knight S, Yu J, Stegeman S, Collier LS, ten Hoeve JJ, de Ridder J, Klein AP, Goggins M, Hruban RH, Chang DK, Biankin AV, Grimmond SM, Australian Pancreatic Cancer Genome Initiative, Wessels LF, Wood SA, Iacobuzio-Donahue CA, Pilarsky C, Largaespada DA, Adams DJ and Tuveson DA

    Nature 2012;486;7402;266-70

Funding

This research was supported by the University of Cambridge and Cancer Research UK, The Li Ka Shing Foundation and Hutchison Whampoa Limited, the NIHR Cambridge Biomedical Research Centre, and the NIH.

Participating Centres

A list of participating centres can be found in the paper.

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