Genes Responsible for Glioblastoma Cell Development Identified

Summary: Study reveals the ZNF117 gene is a major regulator of glioblastoma tumor cells.

Source: Yale

A recent research paper published in Nature Communications by a team led by Yale School of Medicine researchers finds a promising way to make brain cancer cells more susceptible to chemotherapy.

Glioblastoma is the most common malignant brain and CNS tumor, accounting for almost half of all cases. It’s an aggressive disease, with no improvement in survival rates in the last three decades, despite advances in medicine. The overall five-year survival rate is less than four percent. One reason is that the drugs currently available don’t efficiently kill the brain cancer cells.

The only chemotherapy treatment available for glioblastomas is Temozolomide, but it does not kill cancer stem cells. By the time the stem cells have developed into mature cancer cells, they replicate very quickly, and drugs have a limited effect. However, recent research points to a promising breakthrough.

In the paper published in Nature Communications, titled “ZNF117 Regulates Glioblastoma Stem Cell Differentiation Towards Oligodendroglial Lineage,” researchers found a way to trigger glioblastoma stem cells to mature into cancer cells, which can be killed through drugs such as Temozolomide.

This approach would cause fewer side effects in patients and has been proven to be effective in treating other cancers such as leukemia.

The researchers first developed a novel technique to identify all the genes responsible for triggering glioblastoma stem cells to develop into mature cancer cells.

Using an image-based genome-wide RNAi screen, combined with single-cell RNA sequencing, researchers observed the whole range of genes responsible for the development of brain cancer stem cells, rather than a predetermined set of genes, which was previously the case in genome-wide RNAi screen by itself.

The researchers identified the gene ZNF117 as a major regulator of tumor cells that develop into oligodendrocyte-like tumors from the screening. Suppressing the ZNF117 gene is a promising way to trigger cancer cells to develop into a more mature form, making them more susceptible to chemotherapy.

The findings were initially found in vitro but confirmed through mouse models.

This shows a brain
Glioblastoma is the most common malignant brain and CNS tumor, accounting for almost half of all cases. Image is in the public domain

“Brain cancer treatment has had a limited effect,” says Dr. Jianbing Zhou, Ph.D., associate professor of neurosurgery at the Yale School of Medicine and lead author. “There’s a lot of room for improvement. This research potentially suggests an innovative pathway to glioblastoma treatment.”

Dr. Zhou says that while implementing these findings into drug form may take many more years, these findings can be used in conjunction with CRISPR technology, a therapy used for gene editing, to make chemotherapy more effective.

“The work described in this paper represents many years of steady and creative work,” says Mark Saltzman, Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology at Yale School of Engineering and Applied Science and a contributor on the paper.

“The paper describes a series of careful studies that step-by-step show how to go from identification of candidate genes to finding legitimate targets that can be used to alter the course of this deadly disease.”

About this brain cancer research news

Author: Press Office
Source: Yale
Contact: Press Office – Yale
Image: The image is in the public domain

Original Research: Open access.
ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage” by Jun Liu et al. Nature Communications


ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage

Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage.

However, regulation of GSC differentiation towards the neuronal and oligodendroglial lineages is largely unknown.

To identify genes that control GSC differentiation to all three lineages, we performed an image-based genome-wide RNAi screen, in combination with single-cell RNA sequencing, and identified ZNF117 as a major regulator of GSC differentiation.

Using patient-derived GSC cultures, we show that ZNF117 controls GSC differentiation towards the oligodendroglial lineage via the Notch pathway. We demonstrate that ZNF117 is a promising target for GSC differentiation therapy through targeted delivery of CRISPR/Cas9 gene-editing nanoparticles.

Our study suggests a direction to improve GBM treatment through differentiation of GSCs towards various lineages.

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