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Archive - Apr 16, 2019

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Massive Amount of Possible New Target Information Generated in Gene-by-Gene, Genome-Wide CRISPR-Cas9 Screen of Patient-Derived Glioblastoma Cancer Stem Cells; One Existing, Potentially Helpful Small Molecule Drug Identified

Glioblastoma is one of the most devastating forms of cancer, with few existing treatment options. It is also a leading cause of cancer-related death in children and young adults. Scientists have “reverse engineered” brain cancer stem cells gene by gene, uncovering multiple potential targets for this hard-to-treat cancer. This work is a collaboration among the University of Toronto, The Hospital for Sick Children (SickKids), and the University of Calgary. Findings were published online on April 16, 2019 in Cell Reports, making this the first published study to systematically profile a large panel of patient-derived brain tumor cells that have stem cell properties. The open-access article is titled “Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.” "We think that, in one big experiment, we have uncovered many new targets for glioblastoma, some of which were surprising," says Peter Dirks (photo), MD, PhD, co-principal investigator of the study, 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." The research team also found that adult glioblastoma cells are actually dependent on the same genes that are important for brain development in infancy and early childhood. "This really emphasizes how much research needs to be done to understand the developing human brain," says Dr. Dirks, who, in 2003, was the first to discover the existence of cancer stem cells in brain tumors.

New Role Discovered for Innate Immune Sensor NLPR12: Suppressing Liver Cancer

Researchers at the University of Texas (UT) Southwestern have found that a protein in the body’s innate immune system that responds to gut microbes can suppress the most common type of liver cancer. The study, published online on April 16, 2019 in eLIFE, determined that NLRP12 (Nod-like receptor family pyrin domain containing 12), an innate immune sensor, has a protective effect against hepatocellular carcinoma (HCC), a deadly human cancer associated with chronic inflammation. The open-access article is titled “NLRP12 Suppresses Hepatocellular Carcinoma Via Downregulation of c-Jun N-Terminal Kinase Activation in the Hepatocyte.” HCC is responsible for more than 80 percent of liver cancers in the U.S. It is the third-leading cause of cancer-related deaths worldwide and the ninth-leading cause in America, according to the National Cancer Institute. NLRP12 is a member of the NOD-like family of pattern recognition receptors that help the body sense microbes and other stimuli within the cell to regulate the innate immune response – the body’s first line of defense against infection – in multiple ways. This latest work adds to a growing body of evidence connecting inflammation and the development of tumors in the liver. “In this study, we demonstrated that NLRP12 responds to gut microbes and plays a critical role in suppressing a common form of liver cancer,” said Hasan Zaki (at left in photo), PhD, Assistant Professor of Pathology at UT Southwestern and corresponding author of the study. Major risk factors for HCC include hepatitis B or C viral infection, chronic alcohol abuse, and nonalcoholic fatty liver disease, a condition increasing worldwide along with obesity. Although the precise mechanisms through which these conditions induce liver cancer are unknown, inflammation in the liver is considered a key player.