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Insight in derailing cancer cell offers new clues for drug development

Clumping proteins disable anti-cancer- network


Scientists at UMC Utrecht and Utrecht University have discovered that genetic changes in the DNA of cancer cells can lead to the formation of small protein aggregates. These aggregates subsequently disable a whole network of tumour-suppressing proteins, thereby causing cancer growth. This new insight in how cancer cells derail may fuel novel strategies for cancer treatment. The results of this study appeared this week in Nature Structural and Molecular Biology. The study was led by cell biologist Dr. Madelon Maurice of UMC Utrecht and biomolecular chemist Dr. Stefan Rüdiger from Utrecht University.

Cancer can be caused by mutations in genes that regulate the generation of new cells. The generation of new cells is carefully stimulated or inhibited by a network of proteins. Until now, it was generally accepted that one of the mutations deactivates the tumour-suppressing Axin protein. However, the scientists in Utrecht have discovered that the mutated Axin protein changes shape and forms small aggregates. “We observed that large protein tentacles stick out of the protein aggregates to trap and switch off a number of other tumour-suppressor proteins”, explains Dr. Stefan Rüdiger, biomolecular chemist at Utrecht University. “So this is how a single gene mutation can deactivate a large group of cell-growth suppressing proteins.” 

Therapeutic value
The scientists were able to prevent protein aggregation by inserting a second mutation, which also restored the tumour-suppressing role of the Axin protein. “This discovery presents new possibilities for treating certain cancer cases with drugs that prevent protein aggregation”, says Dr. Madelon Maurice, cell biologist at UMC Utrecht. “We know protein aggregates play a role in other diseases, such as Alzheimer and mad cow disease (BSE). We expect that our new findings will help obtain more general insights into how aggregates alter cellular behaviour, which will in turn lead to novel research strategies for treatment.”

High Potential Grant
In 2006, Madelon Maurice and Stefan Rüdiger received a Utrecht University High Potential Grant to initiate this line of research. Utrecht University instituted the High Potential Program to encourage and reinforce innovative and excellent research programs.

Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network
Researchers from Utrecht University involved in the project: Tobias Madl, Teck Yew Low, Albert Heck, Rolf Boelens and Stefan Rüdiger. Researchers from UMC Utrecht: Zeinab Anvarian, Eline van Kappel, Maureen Spit, Ingrid Jordens, Revina van Scherpenzeel, Ineke Kuper and Madelon Maurice.Nature Structural and Molecular Biology, doi:10.1038/nsmb.3191.


Life Sciences
This study is part of Utrecht University’s strategic research theme Life Sciences, subtheme Cancer. This subtheme focuses on the molecular research into cancer, the role of cancer stem cells in the development of tumours and the personalised treatment of cancer.


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