Genes that cooperate with known cancer 'drivers' to promote tumor
formation in the fruit fly are pointing the way to equivalents in humans.
A study of fruit fly genes reveals how molecules cooperate to induce
tumor formation
Cancer biologists have known for
decades that even the most potent cancer-causing genes do not act alone. Yet,
identifying which combinations of genetic changes can cause a tumor to form and
disease to progress remains a challenge. “The hope is that by understanding
these [combinations], it will be possible to design therapeutic strategies
tailored to the genetic changes in different cancers,” says Stephen Cohen of
the A*STAR Institute of Molecular and Cell Biology (IMCB) and the National
University of Singapore.
Sequencing the genomes of tumors
from cancer patients is one approach to identifying cancer-causing mutations.
The number of mutations can be so large, however, that researchers are left
wondering which mutations are cancer ‘drivers’ and which are innocuous
‘passengers’, Cohen notes.
Taking an alternative approach,
Cohen and his team in Singapore succeeded in identifying cancer-causing genes
in the fruit fly, Drosophila melanogaster, based on function1. The team set out
to find genes that cooperate with known cancer drivers that promote tumor
formation.
They began with a gene linked to
breast and lung cancer, epidermal growth factor receptor (EGFR). Team member
Hector Herranz developed a fly model in which activation of EGFR caused tissue
overgrowth, but these overgrowths did not progress to form tumors. He then
screened for secondary genetic changes that would enhance the ability of EGFR
to produce tumors. Herranz found that co-expression of a microRNA called bantam
with EGFR produced tumors that spread through the body and killed the fly.
As regulatory genes that produce
small RNA molecules, microRNAs typically reduce the expression of other genes,
decreasing their ability to produce proteins. The team therefore searched for a
target of the microRNA whose absence increased the tumor-forming potential of
EGFR. Team member Xin Hong was able to locate it: a gene known as Socs36E. In
the team’s fly model, Socs36E behaved like a tumor suppressor: the deletion of
Socs36E enhanced EGFR-induced tumor formation.
Hong then identified the
corresponding human gene as SOCS5. He found that it also behaved as a tumor
suppressor; SOCS5 cooperated with EGFR in an experimental model of human
cancer.
Studies on human SOCS5 are
ongoing, Cohen explains, but early indications point to a breast cancer link.
Further work by the team will determine whether SOCS5 could be a useful
biomarker.
The A*STAR-affiliated researchers
contributing to this research are from the Institute of Molecular and Cell
Biology, Singapore and the National University of Singapore. The IMCB team
collaborated with researchers at Duke NUS Graduate Medical School.
References
- Herranz, H., Hong, X., Hung, N. T., Voorhoeve, P.
M. & Cohen, S. M. Oncogenic cooperation between SOCS family proteins
and EGFR identified using a Drosophila epithelial
transformation model. Genes & Development26, 1602–1611
(2012). | article
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