Researchers identify genes critical for high grade brain tumour growth.


After generating new brain tumour models researchers at Cedars-Sinai have identified the previous unknown role of a family of genes underlying tumour growth in a wide spectrum of high grade brain tumours.  The researchers state that with these new genetic findings they now plan to develop targeted therapeutics that they hope will one day be used treat patients with high grade brain tumours and increase their survival.  The study is published in the journal Cell Reports.

Previous studies show that high grade brain tumours, known as gliomas, are difficult to treat with only a single digit five-year survival rate. Most patients treated for primary gliomas develop into secondary gliomas, which are almost always fatal.  The team explain that any given tumour can harbor a variety of different combinations of mutations. They go on to add that despite advances in radiation and chemotherapy, there are currently no effective curative regimens for treatment for these diverse tumours.

In the current study the researchers first modeled high grade brain tumours from resident stem cells inside the brain, using a cutting edge method of rapid modeling that can create up to five distinct tumour models within 45 minutes.  After effectively modeling high grade brain tumours the team identified the Ets family of genes as contributors to glioma brain tumours.

The researchers state that these Ets factors function to regulate the behaviour of tumour cells by controlling expression of genes necessary for tumour growth and cell fate. When expression of the Ets genes is blocked, researchers can identify and plan novel treatment therapies.

The team surmise that the ability to rapidly model unique combinations of driver mutations from a patient’s tumour enhances the quest to create precision medicine animal models of human brain tumours.  They go on to conclude that immediate next steps involve testing the function of each individual Ets factor to determine their specific role in tumour progression and recurrence after treatment.

Source:  Cedars-Sinai Medical Center 

 

As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.  Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma.  Danielpour et al 2015.

As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma. Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma. Danielpour et al 2015.

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