Achilles’ Heel of Brain Cancer Identified in Tumor Stem Cells

Few words strike me with more dread than glioblastoma, the name for a very aggressive, incurable cancer of the brain. Although surgery and chemotherapy can help hold off or reverse a glioblastoma’s growth for a while, almost inevitably the tumor comes back along with a terrible prognosis: an average survival time of 12 to 15 months after diagnosis with a less than 5% survival rate beyond five years.

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MRI scans of glioblastoma in the brain of a 15 year-old boy.
Image: Wikipedia

Brain tumor stem cells (BTSCs) are thought to be the culprits behind the cancer’s reoccurrence because of their stem cell-like ability for limitless self-renewal. So the idea is that even a tiny number of BTSCs left behind after treatment will likely to lead to a tumor regrowth and treatment relapse. If researchers can better understand what makes the BTSCs tick, they could find ways to eliminate them and cure this dreadful disease.


Brain tumor stem cells (BTSCs).
Image: Takrima Haque / Arezu Jahani-Asl Laboratory

This week researchers largely from The Ottawa Hospital Research Institute report on the identification of a key piece of BTSCs’ molecular machinery that provides a promising target for novel glioblastoma treatments. The study, published in Nature Neuroscience, focuses on the epidermal growth factor (EGF) cell signaling pathway. In normal cells, the EGF protein binds to the EGF receptor (EGFR) on a cell’s surface which triggers a cascade of protein interactions inside the cell that stimulate cell growth among other things.

EGFRvIII: a cancer stem cell gas pedal stuck to the floorboard
Eventually a given EGF signaling event subsides. But many BTSCs found in glioblastoma tissue samples have a mutant form of EGFR, called EGFRvIII, that permanently switches this signaling pathway into the “on position” even in the absence of EGF. It’s like the gas pedal of a car that gets stuck to the floorboard, causing the car to dangerously accelerate even though no one is pressing on the accelerator.

Previous studies had shown this always-on EGFRvIII growth signal causes abnormally high activation of a messenger protein, STAT3, which in turn hyper stimulates a network of genes that leads to cancerous growth of the tumor stem cells. But it wasn’t clear exactly how this protein carries out the uncontrolled cell division. Through a detailed genetic analysis of BTSCs from several glioblastoma patient samples, the team zeroed in on the oncostatin M receptor (OSMR) as a critical player. This analysis revealed that STAT3 was a natural activator of the OSMR gene and that high levels of both proteins in patient samples correlated to a poorer prognosis.

No OSMR = no tumors
To investigate further, human BTSCs genetically engineered to lack OSMR were injected under the skin of mice and showed an 80% reduction in tumor formation. Injection of similar cells directly into the brains of mice found no tumor formation when OSMR was absent. In an interview posted by Genetic Engineering News, senior author Michael Rudnicki recalled his team’s reaction to this finding:

“Being able to stop tumor formation entirely was a dramatic and stunning result. It means that this protein is a key piece of the puzzle, and could be a possible target for future treatments.”

Three proteins form a vicious cycle toward cancerous growth
Additional experiments testing the interactions between EGFRvIII, STAT3 and OSMR point out where those future treatments should act. Like the screeching audio feedback you hear when a microphone is held too close to a speaker, the team showed these three proteins create a self amplifying signal. In the tumor stem cells, EGFRvIII comes in direct physical contact with OSMR and together these two proteins act as co-receptors to activate STAT3 which, in turn, stimulates the production of OSMR which, in turn, stimulates even more STAT3 production. And so on and so on.

Co-senior author, Azad Bonni, explained how they intend to break up this vicious cycle while also acknowledging these are very early days for developing a treatment:

“The next step is to find small molecules or antibodies that can shut down the protein OSMR or stop it from interacting with EGFR. But any human treatment targeting this protein is years away.”

Watch this video to hear from the study’s first author, Arezu Jahani-Asl, now an assistant professor at McGill university:


Stem cells could offer hope for deadly childhood muscle wasting disease

Duchenne muscular dystrophy (DMD) is a particularly nasty rare and fatal disease. It predominantly affects boys, slowly robbing them of their ability to control their muscles. By 10 years of age, boys with DMD start to lose the ability to walk; by 12, most need a wheelchair to get around. Eventually they become paralyzed, and need round-the-clock care.

There are no effective long-term treatments and the average life expectancy is just 25.

Crucial discovery

Duchenne MD team

DMD Research team: Photo courtesy Ottawa Hospital Research Inst.

But now researchers in Canada have made a discovery that could pave the way to new approaches to treating DMD. In a study published in the journal Nature Medicine, they show that DMD is caused by defective muscle stem cells.

In a news release Dr. Michael Rudnicki, senior author of the study, says this discovery is completely changing the way they think about the condition:

“For nearly 20 years, we’ve thought that the muscle weakness observed in patients with Duchenne muscular dystrophy is primarily due to problems in their muscle fibers, but our research shows that it is also due to intrinsic defects in the function of their muscle stem cells. This completely changes our understanding of Duchenne muscular dystrophy and could eventually lead to far more effective treatments.”

Loss and confused

DMD is caused by a genetic mutation that results in the loss of a protein called dystrophin. Rudnicki and his team found that without dystrophin muscle stem cells – which are responsible for repairing damage after injury – produce far fewer functional muscle fibers. The cells are also confused about where they are:

“Muscle stem cells that lack dystrophin cannot tell which way is up and which way is down. This is crucial because muscle stem cells need to sense their environment to decide whether to produce more stem cells or to form new muscle fibers. Without this information, muscle stem cells cannot divide properly and cannot properly repair damaged muscle.”

While the work was done in mice the researchers are confident it will also apply to humans, as the missing protein is almost identical in all animals.

Next steps

The researchers are already looking for ways they can use this discovery to develop new treatments for DMD, hopefully one day turning it from a fatal condition, to a chronic one.

Dr. Ronald Worton, the co-discoverer of the DMD gene in 1987, says this discovery has been a long-time coming but is both welcome and exciting:

“When we discovered the gene for Duchenne muscular dystrophy, there was great hope that we would be able to develop a new treatment fairly quickly. This has been much more difficult than we initially thought, but Dr. Rudnicki’s research is a major breakthrough that should renew hope for researchers, patients and families.”

In this video CIRM grantee, Dr. Helen Blau from Stanford University, talks about a new mouse model created by her lab that more accurately mimics the Duchenne symptoms observed in people. This opens up opportunities to better understand the disease and to develop new therapies.