Glioblastoma is the most aggressive type of cancer that begins with the brain and develops from astrocytes, star-shaped brain cells that help protect the brain from diseases in the blood and provide the brain’s neurons with nutrients, with around 12,000 cases diagnosed in the United States each year. Glioblastoma cells have more genetic abnormalities than the cells of other types of astrocytoma brain cancer. Now researchers from the University of Virginia (UVA) School of Medicine report they have identified an oncogene responsible for this deadly cancer.
Their study, “A cytoskeleton regulator AVIL drives tumorigenesis in glioblastoma,” is published in Nature Communications and led by Hui Li, PhD, associate professor, pathology, at the University of Virginia School of Medicine and the UVA Cancer Center.
“Glioblastoma is a deadly cancer, with no effective therapies. Better understanding and identification of selective targets are urgently needed. We found that advillin (AVIL) is overexpressed in all the glioblastomas we tested including glioblastoma stem/initiating cells, but hardly detectable in non-neoplastic astrocytes, neural stem cells or normal brain,” the researchers wrote.
“The novel oncogene we discovered promises to be an Achilles’ heel of glioblastoma, with its specific targeting potentially an effective approach for the treatment of the disease,” stated Li.
Advillin is a sensory neuron-specific actin-binding protein expressed at high levels in all types of somatosensory neurons in early development. It normally helps cells maintain their size and shape. But the researchers found the gene can be shifted into overdrive by a variety of factors causing cancer cells to form and spread.
“Glioma patients with increased AVIL expression have a worse prognosis. Silencing AVIL nearly eradicated glioblastoma cells in culture, and dramatically inhibited in vivo xenografts in mice, but had no effect on normal control cells. Conversely, overexpressing AVIL promoted cell proliferation and migration, enabled fibroblasts to escape contact inhibition, and transformed immortalized astrocytes, supporting AVIL being a bona fide oncogene,” noted the researchers.
“AVIL is overexpressed in 100% of glioblastoma cells and clinical samples, and is expressed at an even higher level in so-called glioblastoma stem cells, but hardly expressed in normal cells and tissues,” said Li. “Silencing the gene wiped out glioblastoma cells in culture and prevented animal xenografts, while having no effect on normal control cells. Clinically, high AVIL expression correlates with worse patient outcome. These findings and classic transformation assays proved AVIL being a bona fide oncogene,” Li added.
The team provided evidence that the tumorigenic effect of AVIL is partly mediated by FOXM1, which regulates LIN28B, whose expression also correlates with clinical prognosis.
The team of researchers was originally studying a rare childhood cancer called rhabdomyosarcoma. But during their research, they discovered an abnormality in the AVIL gene that prompted them to examine adult cancers to see if the gene could be contributing there.
The team hopes their approach can be used to discover other oncogenes, and hopefully leads to new treatments for a variety of cancers.
Their findings offer a new potential therapeutic target for a cancer that is always fatal.