As the 2019 Gordon Research Conference “Wnt Signaling Networks in Development, Disease and Regeneration” approaches, Stanford developmental biology professor Roeland Nusse is continuing more than 30 years of work with the protein Wnt. He leads the Nusse Lab at Stanford in researching the effects and mechanisms of Wnt signaling, which has profound consequences on stem cell fate, tissue regeneration and cancer.
Wnt is found outside of cells, and it binds to cell receptors. Once bound to a receptor, Wnt initiates signal transduction pathways — a way of communicating with other proteins in the cell — that are involved in fundamental biological processes such as gene replication and stem cell proliferation. Stem cells are undifferentiated cells that can replicate and differentiate into specialized cell types and show promise for tissue regeneration.
History of Wnt signaling
In 1982, the gene Wnt1 was identified by Nusse and his postdoctoral mentor, Harold Varmus. Varmus identified the gene int1 in mice, which corresponds with another gene in fruit flies called Wingless. The two names were combined to form Wnt. To Nusse and Varmus’s surprise, the gene showed similarities among different species, demonstrating the significance of Wnt both evolutionarily and functionally.
During this time, there was also scientific interest surrounding embryonic development. Specifically, researchers were concerned with the process of embryonic induction, by which certain cells in an embryo influence behavior in other neighboring cells. One layer of cells would produce a signal, and the neighboring layer would respond by developing into certain tissue and organs.
“That response could mean that these cells receiving the signal would change their fate, and that was very important in an embryo because we have to go from a mass of cells that are all the same to cells that are suddenly different from each other,” Nusse said. “But nobody knew what the signals were. And it turns out that the Wnts are among the most important developmental signals.”
At the time, Nusse was studying how breast cancer in mice was regulated, and his work with Varmus demonstrated that a hyperactive Wnt gene caused the cancer.
Such diverse research perspectives led to other Nusse Lab projects, such as researching the mechanisms of signal reception and effects of the genes influenced by Wnt signals.
Current and future research
Even though the full processes involving Wnt signaling are unknown, Nusse said the effects of the signal pathway are profound. In bones, for example, a lack of Wnt signaling causes deterioration. Conversely, excess signals result in strong but somewhat massive bones, according to Nusse.
“I think people find the work interesting because it is implicated in two very important aspects of biomedicine: regeneration of tissues and cancer,” Nusse said.
Today, Nusse’s research focuses on how tissues, specifically in the liver, become organized and controlled by the Wnt signals during tissue restoration. Besides understanding liver damage and regeneration, Nusse is also interested in how Wnt plays a role in hepatoblastoma, a liver cancer that affects children.
“Many different forms of human cancer are the consequences of overactivity of Wnt signaling, including colon cancer,” he said.
Previously, it was found that a small subset of hepatocyte stem cells — the cells that are primarily responsible for liver functions — make use of Wnt signaling to help restore liver tissue when other cells die. Additionally, Nusse’s work has shown that cells in the outer layer of blood vessels are responsible for generating Wnt signals.
“[We are trying] to understand why the endothelial cells make Wnt and whether [this occurs] after particular alterations in the system,” Nusse said. “For example, when there’s excess damage to the liver, these endothelial cells making Wnt somehow are changed and start to hyperactivate Wnt signals, and all of this is under tight control. And it is the control mechanisms that we are trying to understand.”
Tissue restoration involves stem cells that are controlled by Wnt, but there is another side to Wnt activity that can result in cancer. Genetic changes in the Wnt signal can cause stem cells to proliferate indefinitely, leading to cancer. Nusse wants to understand exactly how Wnt signals, in the liver specifically, result in both aspects of cellular activity.
“Wnt signaling has pretty profound and broad implications in developmental biology, cancer and other diseases,” said developmental biology Ph.D. candidate Ellen Rim.
Rim studies signal interpretation at the receiving cell. On a day-to-day basis, she takes care of cell cultures and images them to look for proteins involved in the Wnt pathway.
“I’m looking at the immediate downstream molecular events once the signal binds to the receptor,” Rim said. “For example, do the receptor complexes get taken up by the cell? And is that necessary to activate the signaling pathway?”
Developmental biology Ph.D. candidate Teni Anbarchian studies a transcription factor important for liver development and function pertaining to stem cells. Transcription factors are proteins that regulate DNA transcription to messenger RNA, which then get translated to become proteins that express genes and have effects throughout the body. Anbarchian deletes parts of the gene coding for the transcription factor and observes the effect on mouse livers.
Although Anbarchian’s research does not directly involve Wnt signals — she studies processes that are downstream of the signaling process — she found that the gene was involved in regulating hepatocyte size. Without the gene, cells get very big and may not divide or metabolize properly. Anbarchian compared the signals to streetlights controlling which streets and alleys each aspect of the cell travels down.
“When you solve one question, many more questions come up,” she said. “A lot of interesting avenues have come up since I started my project, and I’m focusing on a couple of them now.”
Nusse is interested in how the cell cycle affects Wnt signals and the specifics of how Wnt protein receptors function. Although the receptors have been identified, the sequence of cascade events is still unknown.
“The fact that’s pretty fascinating to me is that, despite the broad implications, we don’t understand fully at the very molecular level how the cell sends the signal and the receiving cell takes it and responds to it, and this can be different depending on the context,” Rim said. “There’s still a lot we need to learn about this pathway.”
Contact Jessica Jen at jessicajen23 ‘at’ gmail.com.