Summary: Researchers have identified possible drug targets in stem cells from glioblastoma cancer, giving analysts a novel method of treating this violent brain tumor. By analyzing stem cells derived from individual tumors, scientists found two key battery subtypes responsible for tumor growth, each with distinct vulnerabilities.
The finding could lead to remedies targeting both types, reducing the likelihood of tumor frequency. This study, using CRISPR monitoring across a huge patient test, brings hope for more effective, personalized glioblastoma treatments. If effective, the view was increase therapy response and patient outcome.
Important Facts:
- Two main body types in glioblastoma push tumor growth: development and injury-response.
- Specific genetic vulnerabilities ( OLIG2, MEK, FAK, B1-Integrin ) in these cells may be targeted to halt tumor recurrence.
- This is the largest CRISPR screening of patient-derived glioblastoma plant cells.
Origin: University of Toronto
A team led by researchers at the University of Toronto has discovered fresh targets that could be crucial to the treatment of glioblastoma, a destructive form of brain cancers. Through a biological vulnerability analysis of patient-derived cancer stem cells, which exhibits the variation found in tumors, these goals were found.
The most prevalent form of adult head cancer is glioblastoma. Due to the sensitivity of glioblastoma cancer stem cells, from which tumors develop, to treatment, it is also the most challenging to treat. Cancer stem cells that survive after a cancer is treated continue to develop new cancers that do not listen to more care.
Graham MacLeod, co-first artist on the research and senior research associate of U of T’s Donnelly Centre for Cellular and Biomolecular Research, said,” Glioblastoma lesions have evaded treatment to date because their content is highly adjustable both within and between cancers.”
According to Wikipedia, “tumours vary a lot from person to person, and even within a single tumour there are multiple cell types that exhibit genetic differences.”
The study was  , published recently in the journal , Cancer Research.
The variability among glioblastoma cancer stem cells can be observed across a gradient between two cell subtypes, which is a key finding of the study. On one end is the developmental subtype, which resembles cells in which normal neurodevelopment has gone awry,  , and on the other end is the injury-response subtype, which is an inflammatory state.
The purpose of the study was to identify potential treatment options for each subtype, helping to treat tumors in a more holistic way.
This study follows , earlier research published in , Cell Reports , that identified vulnerabilities in glioblastoma cancer stem cells that impact their sensitivity to chemotherapy.
In order to identify the most prevalent of these vulnerabilities in each of the subtypes, the next step in this line of research was to examine how vulnerabilities in glioblastoma cancer stem cells differ in a large and diverse set of patient-derived cell lines.
The team performed CRISPR/Cas9 screens in glioblastoma stem cell lines from 30 patients, making this the largest screening study of its kind. The patient-derived cell lines were generated by the lab of Peter Dirks, professor of , surgery , and , molecular genetics , and , Chief of the Division of Neurosurgery at SickKids.
The team identified genes in the cancer stem cell samples that could be used to stop the two cell subtypes from growing. A more potent glioblastoma treatment could be combined with drugs that can target both cell subtypes at once.
A small number of immortalized cell lines are grown in serum for a large portion of the research on glioblastoma, according to Fatemeh Molaei, co-first author on the study and graduate student at the Donnelly Centre and Leslie Dan Faculty of Pharmacy.
” These cells are n’t the best model because they do n’t quite resemble real glioblastoma cells as much as we would like,” said one researcher. Because our cell lines are derived directly from a large group of patients, the findings from our study better reflect what we see in a patient’s tumour.  ,
The OLIG2 and MEK genes were identified as drug targets for the developmental cell subtype and the FAK and B1-Integrin genes as target genes for the injury-response subtype, according to our screening of this group of cell lines.
” It’s been established that there are different subtypes of glioblastoma stem cells, but their differences are not being addressed in the clinic,” said , Stéphane Angers, principal investigator on the study and director of the Donnelly Centre.
” In the future, our results will help in designing new treatments that are tailored to patients by targeting the predominant cell subtype, or both subtypes simultaneously,” said Angers, who is also a professor in the , Leslie Dan Faculty of Pharmacy , and U of T ‘s , Temerty Faculty of Medicine.  ,
The glioblastoma’s greatest strength and greatest challenge is its capacity to adapt to therapeutic treatment. Our study expands our understanding of this particular type of cancer and suggests a different way of treating it, which should hopefully improve the health of the patient.
Funding: This research was supported by the Canadian Institutes of Health Research.
About this news from brain cancer research
Author: Anika Hazra
Source: University of Toronto
Contact: Anika Hazra – University of Toronto
Image: The image is credited to Neuroscience News
Original Research: Closed access.
Graham MacLeod and al.,” Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities.” Cancer Research
Abstract
Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities
Glioblastoma ( GBM ) is the most prevalent and fatal primary brain tumor in adults, and it is caused by self-renewing glioblastoma stem cells ( GSCs ) that persist after therapy and seed treatment refractory recurrent tumors.
A significant obstacle to the development of targeted treatment strategies is the high level of intra- and intertumoral heterogeneity that characterizes GBM tumors. This heterogeneity extends to GSCs that are situated on a gradient between two developmental or injury-response transcriptional states or subtypes. GBM needs effective drug targets for each subtype.
We created the GBM5K targeted gRNA library and performed fitness tests in a total of 30 patient-derived GSC cultures to identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs.
The focused CRISPR screens identified the most prevalent subtype-specific flaws in GSCs and investigated the functional dependency gradient between the developmental and injury-response states.
Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury-response-specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, FAK, MEK and OLIG2.
Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2 ) dependencies between subtypes.
These data provide biological information and a mechanistic understanding of GBM heterogeneity, and they highlight opportunities for precise targeting of defined GBM and GSC subtypes to combat heterogeneity.
