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The most common type of primary malignant brain tumor in adults, glioblastoma is also one of the deadliest cancers, with a median survival rate of 10 to 14 months. Until recently, understanding of glioblastoma growth and survival was limited. Now, scientists report that "reverse engineering" glioblastoma stem cells gene by gene using CRISPR-Cas9 unveiled multiple therapeutic targets to combat treatment resistance, including the SOX transcription factor family.
"We think that, in one big experiment, we have uncovered many new targets for glioblastoma, some of which were surprising," stated one of the study authors, Peter Dirks, MD, PhD, Staff Neurosurgeon and Senior Scientist at SickKids. "These glioblastoma stem cells are also resistant to treatment, which is one reason that these tumors are so hard to cure. We need new ways to disrupt these cells specifically if we are going to give people a better chance of survival."
In the study, published in Cell Reports, the researchers used CRISPR-Cas9 technology to conduct genome-wide screens on 10 patient-derived glioblastoma stem cell cultures. They used this technology to determine which cancer cells were necessary for survival, growth, and ultimately, tumor progression.
"Cancer stem cells fuel the growth of tumors and progression of the disease," said co-principal investigator of the study Stephane Angers, PhD, Associate Professor of Biochemistry at the University of Toronto. "In order to effectively target these cells, having a comprehensive view of the genes controlling the growth programs is critical. If you know which genes are necessary for these cells to survive and proliferate, you can then look at ways to attack or block these genes and stop tumor growth in its tracks."
The researchers discovered 1,007 genes that were present in 6 out of the 10 samples of glioblastoma tumors. In particular, members of the SOX transcription factor family, including the genes SOCS3, USP8, and DOT1L, identified using CRISPR-Cas9 technology, were found to be crucial for glioblastoma stem cell growth.
In addition, the researchers identified the genes modulating resistance to temozolomide, a chemotherapy drug used to treat glioblastoma. They discovered that mutations in the genes MLH1 and MSH2 involved in the mismatch repair pathway (MMR) were found to be responsible for temozolomide resistance. Usually, the MMR pathway is responsible for DNA repair, but if mutations are present in MLH1 and MSH2, DNA repair occurs in cancer cells targeted by temozolomide.
These study results will hopefully help lead to a more effective drug to treat glioblastoma.
For More Information
MacLeod G, Bozek DA, Rajakulendran N, et al (2019). Genome-wide CRISPR-Cas9 screens expose genetic vulnerabilities and mechanisms of temozolomide sensitivity in glioblastoma stem cells. Cell Rep, 27(3):971-986. DOI:10.1016/j.celrep.2019.03.047
Image Courtesy of The Armed Forces Institute of Pathology