Prostate cancer cells under the microscope. (© Lukasz Kacprzyk / DKFZ)
Prostate cancer is the most common cancer in men in Germany with around 63,000 patients diagnosed every year. About half of them have an altered Pten gene. This well-known tumor suppressor gene can help prevent cancer development in healthy people by inducing cell death in tumor cells. However, little is known about which other genes cooperate with Pten to prevent cancer.
In order to find out more, the international team designed a new method. They converted the Pten-Gene in mice into a mobile DNA element known as a transposon. This transposon “jumps” from its original position and lands at a random position throughout the genome, damaging and thus deactivating genes into which it is inserted. The transposons “starting point”, i.e. the Pten-Gene, is deactivated as well. In the experiment, cancers would grow when the transposon damaged a tumor suppressor gene that co-operated with Pten.
“Using the new transposon-based approach, we were able to systematically search the genome for genes cooperating with Pten and influencing the development of prostate cancer, but also other forms of cancer like breast or brain cancer,” says Dr Juan Cadiñanos, joint lead author from the Instituto de Medicina Oncologica y Molecular de Asturias and the Wellcome Trust Sanger Institute in Britain. “This approach could also be used to look into relations between other genes.”
The researchers analysed 278 prostate, breast and skin tumors and revealed hundreds of genes that could cooperate with Pten and act as further tumor suppressor genes. Human cell lines and data from human prostate tumors were then used to study the five most promising genes.”Coupled with Pten inactivation, a loss of function in these genes led to typical cancer pathways being activated,” says Jorge de la Rosa, one of the study’s first authors. The researchers found that in human prostate tumors, the genes in question were considerably limited in their function.
Transposon-based approaches are useful for looking into the molecular basics of the development of tumors. “They allow us to find genes connected to cancer that are hard to find using other methods,” says Roland Rad, a DKTK-Professor for translational Oncology at TUM’s Klinikum rechts der Isar. “In order to understand the biology of tumor development, we must uncover the complex tumor suppressor networks. This is a prerequisite for developing new therapeutic strategies.”
de la Rosa et. al.*: A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes. In: Nature Genetics (20. März 2017) doi:10.1038/ng.3817
* The two first and four last authors have contributed equally to this publication.