Source: Virginia Commonwealth University
Summary: Researchers believe that they have uncovered an “Achilles heel” of glioblastoma multiforme (GBM), the most common and deadly form of brain cancer.
Autophagy is a process in which cells get rid of unnecessary or dysfunctional components. It can be toxic to the cells, or it can serve a protective role. Protective autophagy allows glioma stem cells to resist anoikis, which is a form of programmed cell death (apoptosis) that occurs when cells detach from the extracellular matrix, or the collection of molecules that help support and protect cells within the body. Researchers from the Virginia Commonwealth University found that this protective mechanism is regulated by the gene MDA-9/Syntenin. They discovered that when the expression of MDA-9/Syntenin is blocked, glioma stem cells lose their ability to induce protective autophagy and succumb to anoikis, resulting in cancer cell death. The study findings were published in the journal Proceedings of the National Academy of Sciences.
The team found that MDA-9/Syntenin maintains protective autophagy by activating BCL2, a gene that regulates cell death. Additionally, they showed that MDA-9/Syntenin suppresses high levels of autophagy that would be toxic to the cell through epidermal growth factor receptor (EGFR) signaling. Excessive EGFR signaling has been shown to contribute to tumor growth in a wide variety of cancers. Using GBM cells from patients who underwent surgical removal of their tumors, the scientists demonstrated the loss of these protective biological functions in the absence of MDA-9/Syntenin through laboratory experiments involving glioma stem cell cultures. These findings were then tested in mouse models of human stem cells, where an increase in survival occurred following MDA-9/Syntenin inhibition.
Paul B. Fisher said, “This is the first study to define a direct link between MDA-9/Syntenin, protective autophagy and anoikis resistance. We’re hopeful we can exploit this process to develop new and more effective treatments for GBM and possibly other cancers.”
More information: Sarmistha Talukdar et al. MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1721650115