Glioblastoma associated with post-traumatic brain healing

The results of a study by Canadian researchers show that the healing process that follows brain damage, such as trauma, infection, and stroke, is glioblastoma when new cells are created to replace cells lost by the damage due to mutations. It suggests that it may promote the growth of glioblastoma tumors. Findings reported by a team of interdisciplinary researchers at the University of Toronto, Hospital for Sick Children (SickKids), and Princess Margaret Cancer Center develop new approaches to treat the most difficult glioblastoma. May lead to-treating adult brain cancer.

“Our data suggest that changes in the correct mutations in certain cells in the brain can change with injury and cause tumors,” said the director of neurosurgery. Said Peter Darks, MD, a senior scientist in neurosurgery. Development and Stem Cell Biology Program at Sick Kids. “Glioblastoma can be thought of as an unstoppable wound. We are excited to tell us how it develops and grows, and the injury and inflammatory response. By focusing on, we open up entirely new ideas about treatment. “

The researchers are led by Darks, Dr. Gary Bader, a professor of molecular genetics at the Donnelly Cell Biomolecules Research Center in the Medical Sciences Building, University of Toronto, and Dr. Trevor Pew, a senior scientist at Princess Margaret.Reported their findings in Nature Cancer, “Gradient transcriptional state of developmental and injury response defines functional fragility that underpins glioblastoma heterogeneity.. Dirks is the Dream Team Leader of the Pan-Canada Stand Up To Cancer Canada Dream Team, which focuses on glioblastoma.

The authors state that glioblastoma is one of the most aggressive and refractory brain tumors in adults. Patients with glioblastoma currently have limited treatment options available, with a life expectancy of only 15 months after diagnosis. “Treatment failure is rooted in the widespread heterogeneity observed within the tumor and between patients,” the team further commented. “Glioblastoma has a diverse cell population, including the rare glioblastoma stem cells (GSCs) that promote tumorigenesis.”

The Dirks team has previously shown that GSC is involved in the development and recurrence of tumors after treatment, and in a reported study, the team aimed to characterize the diversity of this GSC fraction. I was there. To do this, they applied the latest single-cell RNA sequencing and machine learning techniques to map the molecular composition of GSCs cultured from tumors in 26 patients.

The team expanded patient-derived GSC in the lab to obtain a sufficient number of rare cells for analysis. Approximately 70,000 cells were analyzed using single-cell RNA-seqing technology, which detects which genes are turned on in individual cells. The effort was led by co-author Laura Richards, a graduate student in Pew’s lab.

The resulting data confirmed widespread disease heterogeneity. This means that existing treatments cannot wipe out all the different subclones, so each tumor contains multiple subpopulations of molecularly different cancer stem cells, increasing the likelihood of recurrence. “The goal is to identify drugs that kill glioblastoma stem cells,” said graduate student Owen Whitley, who helped analyze the computational data. “But in order to be able to target these cells more effectively, we first needed to understand the molecular properties of these cells.”

Interestingly, the results highlighted a subpopulation of GSC that had the molecular characteristics of inflammation and was mixed with other cancer stem cells within the patient’s tumor. These findings are years before some glioblastomas become symptomatic in patients when mutations disrupt the normal tissue healing process that produces new cells that replace cells lost due to injury. It has been shown that it begins to form when it can become. When mutant cells are involved in wound healing, they cannot stop growing because normal controls do not work, which can promote tumor growth.

A closer look reveals that each tumor exhibits one of two different molecular states that the author called “development” and “injury response”, or somewhere in the gradient between the two. It was. The developmental state is characteristic of glioblastoma stem cells and resembles that of stem cells that are rapidly dividing in the prenatally growing brain. The second condition was surprising to researchers who described the injury response, as it showed an immune pathway that indicates the wound healing process and up-regulation of inflammatory markers such as interferon and TNFalpha. These immune signatures were detected by single-cell technology, but were overlooked by older methods of bulk cell measurement.

Additional experiments led by Stephen Angers’ lab at Lesliedan Pharmacy proved that the two states were vulnerable to different types of gene knockout, an inflammation that was not previously considered for glioblastoma. We have revealed a band of therapeutic targets related to.

The study also found that the relative mixture of the two conditions was patient-specific and that each tumor was biased towards either the developmental edge of the gradient or the injury-responsive edge. “Each patient’s GSC was composed of multiple subpopulations that were transcriptionally and genetically distinct, but all GSCs were single across two recurrent cell states defined by the neurodevelopmental and inflammatory programs. It has converged on the biological axis, “the researchers say.

They are now trying to turn these prejudices into adjusted treatments. “… The heterogeneity found at the GSC level suggests the need to develop treatments that simultaneously target both the developmental and inflammatory processes observed in GBM and GSC.” Ontario Cancer Pew, who is also the institute’s genomics director, explains: “We are currently looking for drugs that are effective at various points on this gradient. Here, a drug cocktail that can analyze a patient’s tumor at the single-cell level and simultaneously extract multiple cancer stem cell subclones. There is a real opportunity for precision medicine to design. “

As the authors conclude, “Glioblastoma proposes to grow from a basic GSC-based nerve wound response transcription program, a promising target for the development of new therapies … our job is , Explains the causes of cellular heterogeneity in GBM and provides a model to identify the various sensitivities of this basic cellular program, which directly informs the development of new therapeutic strategies targeting GBM. “