A new study based on a collaboration among researchers at Yale, Tongji University in China and La Trobe University in Australia has found a new key regulator for a cellular pathway involved in tumor growth.
The researchers found that a molecule called POSH is able to deactivate a signaling pathway called Hippo that, when active, allows tumors to grow. The Hippo pathway relies on communication between several different molecules, and the researchers found that POSH breaks down one of these molecules, shutting down the pathway. The study was published in the Proceedings of the National Academy of Sciences on Feb. 12.
“The reason we are interested in this project is because a lot of signaling pathways are conserved,” said Xianjue Ma, a postdoctoral fellow at Yale and one of the study’s lead authors. “The one that I’m studying is a major regulator of tumor growth and proliferation. The goal is to find genes that control the pathway and find some clues for how it affects the pathway in humans.”
Deregulation of cellular signaling pathways is a common theme underlying human cancer. The Hippo pathway is a well-studied pathway normally involved in regulating tissue growth and proper organ size, according to the study. When abnormally regulated, however, it can instead promote the growth of tumors.
To study the pathway, the researchers used fruit flies as a model organism.
“Many people use mice or cancer cells,” Ma said. “Fruit flies are also a very useful organism to study the pathway to find new [cancer-causing genes]. By studying the fruit fly as a model, we can still answer a lot of questions related to human cancer biology.”
Many human genes have relatives in fruit flies, meaning they were preserved through evolution with few changes. As a result, simpler organisms that are easier to experiment on than humans, like fruit flies, can actually provide key insights into human disease. Fruit flies are inexpensive, easy to manipulate genetically and easy to study in a lab, making them an attractive model organism.
To find possible regulators of the Hippo pathway, the researchers employed a commonly used procedure: a genetic screen. In a genetic screen, researchers generate a series of mutations in a specific pathway — here, Hippo — to see which parts of that pathway are affected. If the pathway deactivates when a molecule mutates, for example, then researchers can intuit that the molecule likely plays a role in regulating the pathway.
“The major component was identified through a genetic screen,” Ma said. “We identified POSH as a potent regulator of the Hippo pathway.”
POSH is part of a family of proteins called E3 ubiquitin ligases, which degrade other molecules. In this process, molecules set to be broken down are “tagged” with a string of ubiquitin molecules. E3 ubiquitin ligases tag the targeted molecule like a baggage assistant at an airport does with luggage, leading to the molecule’s degradation.
In the Hippo pathway, POSH degrades one of its upstream components, called Expanded, or Ex for short, causing the Hippo pathway to become inactivated, according to the study.
This finding, researchers said, poses a new set of questions in the field of cancer biology.
“Now, we want to see if the mechanism is conserved in mammals,” Ma said. “It will be very interesting to dissect if homologs in humans regulate the human pathway.”
The team’s next steps will involve looking at the human genome to see how the study’s results translate to human disease, specifically cancer. Previous studies, such as one published in the journal Cancer Letters, have shown that the Hippo pathway is involved in human lung cancer.
One challenge in cancer research has been the development of resistance to existing therapies, especially therapies that seek to block cellular pathways. Cells are often able to activate other pathways to mitigate the effects of a particular therapy.
“Biology is far more complicated — there is a lot of redundancy,” said Warren Kibbe, current chief of Translational Biomedical Informatics at the Duke Cancer Institute and former deputy director of the National Cancer Institute. “In the next 20 years, it will be about understanding how biological resiliency is turned against itself in disease states.”
More Americans die from lung cancer each year than from any other form of cancer, according to the Centers for Disease Control and Prevention.
Vikram Shaw | vikram.shaw@yale.edu