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Brain Cancer Cells "Reverse Engineered" Using Genome-Wide CRISPR-Cas9 Screens.

TORONTO, Ont., Canada, April 16, 2019 -- One of the most devastating forms of cancer, glioblastoma is a leading cause of cancer-related death in children and young adults and has few treatment options.

Now 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 between the University of Toronto, the Hospital for Sick Children (SickKids), and the University of Calgary.

The study is the first to systematically profile a large panel of patient-derived brain tumor cells that have stem cell properties.

"We think that, in one big experiment, we have uncovered many new targets for glioblastoma, some of which were surprising," said Peter Dirks of 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 researchers also found that adult glioblastoma cells are actually dependent on the same genes that are important for brain development in infancy and early childhood.

The emergence of the CRISPR-Cas9 technology provides a powerful new way to explore cancer biology through genome-wide screens.

Taking 10 unique patient-derived glioblastoma stem cell cultures, CRISPR "cell fitness screens" were used to determine which genes in the cancer stem cells were required for the cells to survive and to grow, and therefore were important for tumor progression.

Cancer stem cells fuel the growth of tumors and progression of the disease.

To effectively target these cells, having a comprehensive view of the genes controlling the growth programs is critical.

Knowing which genes are necessary for these cells to survive and proliferate, allows examination of ways to attack or block these genes and stop tumor growth in its tracks.

By systematically knocking out each of the 20,000 genes, one at the time, from each of the 10 patient samples, the researchers found multiple genetic vulnerabilities and revealed a wealth of data that can be further mined to identify possible drug targets for glioblastoma.

This is one of the first studies of its kind, where CRISPR screens are performed directly in multiple freshly-isolated patient cells in parallel.

A massive amount of new information was developed that the research community can now interrogate to help design new treatment strategies.

One gene identified in the study, known as DOT1L, was found to be necessary for tumor persistence in seven of the 10 glioblastoma patient tumor cultures.

The researchers used preclinical models to demonstrate the effectiveness of a drug now used to treat leukemia to inhibit the DOT1L gene product in glioblastoma stem cells.

Blocking this specific protein in this particular form of brain cancer reduced tumor growth and resulted in longer survival in the preclinical model, a promising advancement because it uncovered a biological process not previously suspected to be implicated in glioblastoma, for which a small molecule drug already exists.

In recent years, significant time, effort and funding dollars have been spent on the genomic sequencing of cancer tumors.

While this has provided a clearer picture of the hundreds of genetic mutations present in glioblastoma and other cancers, for glioblastoma it has not led to any significant treatment advances, Angers said.

"This shows that just knowing about genetic mutations is not enough," said Graham MacLeod, a co-first author. "That is a static picture of cancer. We are learning that we need to better understand the blueprint of how this cancer functions and what specific genes fuel tumor growth in order to attack it."

Citation: Graham MacLeod et al., Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells. Cell Reports, 2019; 27 (3): 971 DOI: 10.1016/j.celrep.2019.03.047


Contact: Peter B. Dirks,
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Publication:Stem Cell Research News
Date:Apr 22, 2019
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