Brain’s Own Activity Can Fuel Growth of Deadly Brain Tumors, CIRM-Funded Study Finds

Not all brain tumors are created equal—some are far more deadly than others. Among the most deadly is a type of tumor called high-grade glioma or HGG. Most distressingly, HGG’s are the leading cause of brain tumor death in both children and adults. And despite extraordinary progress in cancer research as a whole, survival rates for those diagnosed with an HGG have yet to improve.

shutterstock_30402241

But recent research from Stanford University scientists could one day help move the needle—and give renewed hope to the patients and their families affected by this devastating disease.

The study, published today in the journal Cell, found that one key driver for HGG’s deadly diagnosis is that the tumor can be stimulated to grow by the brain’s own neural activity—specifically the nerve activity in the brain’s cerebral cortex.

Michelle Monje, senior author of the study that was funded in part by two grants from CIRM, was initially surprised by these results, as they run counter to how most types of tumors grow. As she explained in today’s press release:

“We don’t think about bile production promoting liver cancer growth, or breathing promoting the growth of lung cancer. But we’ve shown that brain function is driving these brain cancers.”
 


By analyzing tumor cells extracted from HGG patients, and engrafting it onto mouse models in the lab, the researchers were able to pinpoint how the brain’s own activity was driving tumor growth.

The culprit: a protein called neuroligin-3 that appeared to be calling the shots. There are four distinct types of HGGs that affect the brain in vastly different ways—and have vastly different molecular and genetic characteristics. Interestingly, says Monje, neuroligin-3 played the same role in all of them.

What was so disturbing to the research team, says Monje, is that neuroligin-3 is an essential protein for overall brain development. Specifically, it helps maintain healthy growth and repair of brain tissue over time. In order to grow, HGG tumors hijack this critical protein.

The research team came to this conclusion after a series of experiments that delved deep into the molecular mechanisms that guide both brain activity and brain tumor development. They first employed a technique called optogenetics, whereby scientists use genetic manipulation to insert light-sensitive proteins into the brain cells, or neurons, of interest. This allowed scientists to activate these neurons—or deactivate them—at the ‘flick of a switch.’

When applying this technique to the tumor-engrafted mouse models, the team could then see that tumors grew significantly better when the neurons were switched on. The next step was to narrow it down to why. Additional biochemical analyses and testing on the mouse models confirmed that neuroligin-3 was being hijacked by the tumor to spur growth.

And when they dug deeper into the connection between neuroligin-3 and cancer, they found something even more disturbing. A detailed look at the Cancer Genome Atlas (a large public database of the genetics of human cancers), they found that HGG patients with higher levels of neuroligin-3 in their brain had shorter survival rates than those with lower levels of the same protein.

These results, while highlighting the particularly nefarious nature of this class of brain tumors, also presents enormous opportunity for researchers. Specifically, Monje hopes her team and others can find a way to block or nullify the presence of neuroligin-3 in the regions surrounding the tumor, creating a kind of barrier that can keep the size of the tumor in check. 


The Man Behind the Curtain: Protein Helps Keep Cancer Cells Alive and Kicking

Being diagnosed with brain cancer comes with a sobering sentence: even with the most aggressive treatments, life expectancy for the most common form of brain cancer—called glioblastoma—is less than two years.

One of the key culprits, many scientists now believe, are cancer stem cells. Cancer stem cells are a subset of cancer cells that have three very unique properties: they can self-renew, they can propagate (or multiply) the cancer, and they can transform into the many types of cells that are found in a tumor.

shutterstock_118491940

Cancer stem cells are a relatively new concept, but they have generated a lot of excitement among cancer researchers because they could lead to the design of more effective therapies. And while whether or not they even existed has long been a source of debate among experts, a series of recent research findings have bolstered the notion not only that they exist, but also that they play a significant role in the recurrence of some forms of cancer—including glioblastoma.

Researchers have been identifying, step by step, the many proteins and chemical pathways that form the path from cancer stem cell to tumor. Previous research had found the CDK class of proteins to be present in large quantities in mature cancer cells in patients suffering from glioblastoma. But they suspected something else was at play, helping to keep the CDK proteins switched on in mature cancer cells.

So scientists at McGill University in Canada, led by neurologist Dr. Anita Bellail, dug deeper. In their report, published this week in the journal Nature Communications, the team has pinpointed a new class of proteins at play behind the scenes called SUMO.

Specifically, Bellail and her team observed that the SUMO1 protein in particular modifies a CDK protein called CDK6 in a process the team has dubbed ‘sumylation.’ As Bellail explained in this week’s news release:

“CDK6 sumylation inhibits its degradation and thus stabilizes the CDK6 protein in the cancer.”

In other words, the CDK6 protein does not by itself maintain a presence in the cancer cells. Instead, it requires a little help from SUMO1. As Bellail continued:

“We found that CDK6 sumylation is required for the renewal and growth of the cancer stem cells in glioblastoma.”

It stands to reason, therefore, that shutting off SUMO1 could do the reverse—thus destabilizing CDK6 and, potentially, block the progression of the cancer.

And in further experiments by Bellail and her team, they found exactly that.

These results hold significant promise for finding new ways to treat glioblastoma because now the team has a target: SUMO1. In fact, the research team is now screening for drugs that can target SUMO1 and block it, thus reducing CDK6 levels and, as a result, cancer cells—and one day offering a more optimistic outcome for those diagnosed with glioblastoma.

Want to learn more about cancer stem cells? Check out our 2009 “Spotlight on Cancer Stem Cells” video starring Dr. Michael Clarke, associate director of the Stanford Institute for Stem Cell and Regenerative Medicine.