Pioneering the Future

Brain Under Fire

For people with a cancer-associated condition called paraneoplastic syndromes, sudden memory loss or a loss of coordination is often the first sign that something is wrong. These and other neurological symptoms can worsen quickly, within weeks or days. Most people with this rare condition develop problems before they even know that a tumor is growing in their body.

Surprisingly, the symptoms are not caused by the cancer itself but rather the immune system’s response to it. As the immune system learns to recognize and destroy tumor cells, it can also begin to target healthy brain cells.

This is because cells in the brain naturally produce proteins that aren’t found on healthy cells elsewhere in the body. It turns out that some tumors produce brain proteins, too. But why do only specific brain proteins made by tumors cause paraneoplastic syndromes? That has been a mystery. 

In the lab of U of U Health neurobiologist Jason Shepherd, PhD, researchers are studying a protein called PNMA2 that is normally expressed in the brain but associated with paraneoplastic syndromes. They found that PNMA2 proteins are released from tumors and brain cells. In both cases, the proteins assemble into a larger structure that resembles similar structures formed by viruses.

When graduate student Junjie Xue injected PNMA2 proteins into mice, it provoked a particularly strong immune reaction—but only when the proteins assembled into the virus-like structure. The immune system reacted as if it were attacking a virus. Strikingly, the mice developed deficits in learning and memory that resembled the neurological symptoms experienced by paraneoplastic patients.

By figuring out exactly how and why the immune system attacks the brain, Shepherd and his team hope to uncover strategies for treating PNMA2 associated paraneoplastic syndrome. “If you can alleviate some of those neurological symptoms, it really would be huge,” he says.

Uncovering Unwanted Fuel for Cancer Growth

When cancer cells grow into tumors, travel through the body, and develop into life-threatening metastases, they do not act on their own. Their behavior is influenced by other nearby cells. Even the immune system, which ordinarily helps keep cancer in check, can produce signals that drive the disease.

Scientists like U of U Health biochemist and Huntsman Cancer Institute investigator Minna Roh-Johnson, PhD, are intent on figuring out exactly how a type of cell in the immune system called a macrophage can promote cancer’s growth and spread. It’s a first step toward developing treatments that block those dangerous interactions.

Researchers in Roh-Johnson’s lab have uncovered a surprising way macrophages spur on cancer cells. They noticed that mitochondria—energy-generating structures inside cells—are often transferred from macrophages to tumor cells. While many scientists suspected the extra mitochondria might help fuel cancer cells as they grow, Roh-Johnson’s team took a close look and found a more complicated situation.

The researchers painstakingly tracked the behavior and function of the donated mitochondria. They discovered that these mitochondria were dysfunctional—mostly incapable of generating energy. Within cancer cells, the donated mitochondria accumulated highly reactive metabolic byproducts known as reactive oxygen species. This, the researchers found, activated pathways that drive cell growth.

Mitochondria-targeted treatments are under active investigation for various illness. Roh-Johnson says she hopes it might one day be possible to manipulate mitochondrial signals to rein in the growth of cancer cells. 

Movement Disorder Exposed

Spinocerebellar ataxia type 4 (SCA4) is a rare movement disorder whose symptoms—usually difficulty walking and a loss of balance—begin to set in during adolescence or adulthood. As the disease progresses, individuals may experience muscle weakness, lose sensation in their hands and feet, and lose their reflexes.

The condition was first described in Utah families and was also identified in families from the U.S. and Europe, all of whom are likely of Swedish descent. But until recently, its specific genetic cause was not known, because the mutation associated with SCA4 falls within a region of DNA that was particularly difficult to analyze. With the latest DNA sequencing technology, U of U Health scientists led by neurologist Stefan Pulst, MD, were finally able to pinpoint the genetic cause of SCA4: a stretch of repetitive DNA in a gene called ZFHX3 that is longer than it should be.

It took researchers 25 years to uncover the mutation, but already that knowledge provides relief for patients and their families. Now they can undergo genetic testing to determine if they or their children are likely to develop the disorder. The discovery has also enabled Pulst and his team to dig into exactly why the genetic change is toxic for neurons, which they hope will help develop an effective treatment.

“The only step to really improve the life of patients with inherited disease is to find out what the primary cause is,” Pulst says. “We now can attack the effects of this mutation potentially at multiple levels.”

The team’s experiments suggest one effect is an impaired ability to recycle unwanted cellular debris inside neurons. A drug designed to overcome this type of defect is already being tested in clinical trials for another movement disorder, SCA2. Given the similarities they have uncovered, the researchers say it’s possible that treatment might also benefit patients with SCA4.