The discovery of an odd couple of genes that team up to trigger rare and difficult-to-detect gastrointestinal stromal tumors could eventually lead to better diagnostics and treatments.
A veritable “odd couple” of genes—one altered, one normal—team up to trigger rare and difficult-to-detect gastrointestinal stromal tumors, or GIST. The discovery of this unexpected genetic teamwork could eventually lead to better diagnostics and treatments for this form of cancer, says Howard Hughes Medical Institute investigator Charles Sawyers, who co-led the work with David Allis of Rockefeller University.
The findings could also help unravel the origins of a far more common cancer, says Sawyers, since one of the genes responsible for GIST is also a key player in prostate cancer.
While looking at ETV1 across a large swath of cancers available in online data sets, we stumbled upon this finding that GIST tumors uniformly make a lot of ETV1.
Charles L. Sawyers
The path to the GIST discovery, which was published online October 3, 2010, in the journal Nature, began through studies by the Sawyers group of genetic alterations often seen in prostate cancer. One gene, ETV1, is overactive in many cases of prostate cancer. A data mining exercise conducted jointly by the Sawyers and Allis labs revealed that ETV1 is also expressed at very high levels in GIST tumors.
“While looking at ETV1 across a large swath of cancers available in online data sets, we stumbled upon this finding that GIST tumors uniformly make a lot of ETV1,” says Sawyers, who is also the chair of the human oncology and pathogenesis program at Memorial-Sloan Kettering Cancer Center in New York. Serendipitously, co-authors Ping Chi from the Allis lab and Yu Chen from the Sawyers lab are both oncologists and treat GIST and prostate cancer patients, respectively. “That coincidence, together with the fact that Drs. Chi and Chen are married, allowed us to make progress very quickly,” Sawyers said.
In a series of laboratory experiments, the Sawyers and Allis research teams confirmed that GIST tumors need ETV1 to survive. GIST tumors are spawned when a type of intestinal cell called the interstitial cell of Cajal (ICC) begins to grow in an uncontrolled fashion.
In prostate cancers, a broken form of the ETV1 gene results in abnormally high amounts of its protein. Expected to see something similar in GIST, a surprise emerged. Even normal ICCs produced very high amounts of the ETV1 protein—higher than any other cell type that the Sawyers-Allis team tested—including the prostate cancer cells that carry a mutated version of ETV1.
Experiments in mice lacking ETV1 confirmed that the gene is necessary for normal development of ICCs. Mice without the gene did not produce any of ICC cells in their intestinal tract.
“So that made us think ETV1 is not abnormal in these cells. It’s just that these cells in the gut that give rise to GIST naturally have high levels of ETV1. When those cells become a tumor, they just carry along that high level,” says Sawyers.
But how was ETV1 involved in sparking GISTs? The answer came after Sawyers and his colleagues began examining the effects of another gene, KIT, which goes awry in GIST. KIT makes a cellular signaling protein, and about a decade ago researchers discovered that GISTs need a mutant version of KIT to grow. When they inhibited KIT with a commercially-available drug, imatinib (Gleevec), a connection emerged: Cellular levels of ETV1 also plummeted. It appeared that KIT and ETV1 were somehow cooperating to trigger GISTs.
To find out how the genes were interacting, the Sawyers-Allis team prepared dishes of GIST cells, some with normal KIT and normal ETV1, and others with mutant KIT and normal ETV1. In the cells with mutant KIT, the ETV1 protein hung around inside the cells longer than in cells with normal KIT. In other words, it looked like the mutant KIT was keeping ETV1 from being degraded quickly, as usually happens.
ETV1 is a transcription factor, a master gene that controls the expression of many other genes. “Conceptually, what’s cool about this finding is that we’ve known for decades that transcription factors can be oncogenes,” says Sawyers. “But this is a twist on that theme. Usually, the transcription factor has to be altered to turn it from normal to oncogenic. Here, there’s no alteration at all. The alteration is in KIT, which regulates the stability of the transcription factor. So, KIT sort of hijacks this normal transcription factor.”
About 6,000 people in the United States are diagnosed with GISTs each year, and the tumors are difficult to detect. Sawyers says that the finding that KIT and ETV1 work together could be exploited to develop better molecular detection tests for the disease.
Sawyers is now returning to the disease he originally studied, prostate cancer, and is cataloging the list of genes that ETV1 regulates in both GISTs and prostate cancers. “ETV1 is active in both cancers, so it should have some common targets that are involved of the cancer process,” he says. Identification of such commonalities could provide drug makers with ideas for inhibiting both cancers, Sawyers says.