Laia Simó Riudalbas and Didier Trono first discovered that a previously overlooked gene in the human genome is involved in the spread of colon cancer cells. They then persistently searched for compounds—and succeeded.
Laia Simó Riudalbas and Didier Trono first discovered that a previously overlooked gene in the human genome is involved in the spread of colon cancer cells. They then persistently searched for compounds—and succeeded.
Initially, scientists believed that a section on chromosome 8, with the unpronounceable name POU5F1B, was a useless remnant of an ancient genetic duplication. In other words, it was considered a nonfunctional piece of DNA, or "a dead pseudogene," according to Didier Trono, head of the Laboratory of Virology and Genetics at the École Polytechnique Fédérale de Lausanne (EPFL). However, Laia Simó Riudalbas from his research group discovered that the opposite is true: the gene she encountered in her work, funded by the Swiss Cancer Research foundation, is very much active. Since it is only found in primates, it is at most 15 million years old—quite young from an evolutionary perspective.
The human version of the POU5F1B gene differs from chimpanzee and gorilla versions in only a few details. However, these differences cause the protein encoded by the human POU5F1B gene to move to the cell surface instead of remaining in the cell nucleus. At the surface, the POU5F1B protein forms a complex with other proteins. Simó Riudalbas compares this complex to "microfingers" that "change the cell's gripping properties." Her experiments revealed that this protein complex allows cancer cells to align with fibers in the tissue and break away from the primary tumor.
In other words, the POU5F1B protein appears to facilitate the formation of metastases. As a result, cancer cells with this protein are particularly aggressive and more difficult to combat. Since the chimpanzee and gorilla versions of the POU5F1B protein remain in the nucleus, they do not promote metastasis. This trait seems to be unique to the human variant. The researchers describe this discovery as "the first known oncogene restricted to humans." Trono likens the gene to "a new piece on the chessboard" that could not have been discovered in animal models and that could now be leveraged to fight cancer.
Simó Riudalbas stumbled upon the new oncogene while analyzing a dataset of gene activity based on tissue samples from 301 colorectal cancer patients. She was searching for genes that are rarely active in healthy cells but switched on in cancer cells. "The POU5F1B gene is expressed in only four percent of normal colon cells, but it is active in nearly two-thirds of colorectal cancer samples," says Simó Riudalbas. "And in three-quarters of all metastases examined."
Next, she discovered that the oncogene is not only involved in the spread of colon cancer but is also often active in other tumors, such as those in the stomach, esophagus, prostate, breast, and lungs. Although there is much to investigate, Simó Riudalbas initially focused on colon cancer due to limited resources. To identify compounds that could target and disable the POU5F1B protein, she exposed her cell cultures in the lab to almost 6,000 different substances.
"I thought the endeavor was hopeless and advised her to stop after five or six months," Trono recalls. However, Simó Riudalbas continued her search without informing her supervisor. After more than a year, she finally succeeded. She vividly remembers the moment: "I started sweating and trembling all over."
Upon repeating the experiment, she obtained the same result: she had found three potential drug candidates. Although these compounds do not directly target the POU5F1B protein, they prevent other proteins from stabilizing it. When it degrades more quickly, the POU5F1B protein apparently can no longer assemble its "microfinger complex."
Trono and Simó Riudalbas have since submitted a follow-up project proposal, which was recently approved. They aim to continue their work by introducing POU5F1B as a prognostic biomarker. "This could allow physicians to detect previously overlooked cases of aggressive colon cancer and treat them accordingly," says Simó Riudalbas. They also plan to deepen their research on treating aggressive tumors with the POU5F1B protein, hoping to "pave the way for clinical trials." For Trono, these unexpected and unusual findings have led the research in a completely new direction. "The fact that we can now pursue this work is anything but a given. We are very grateful to the Swiss Cancer Research foundation and its donors for their support."
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