Brain tumors associated with tissue healing

A brain scan showing a top view of a cross section of a glioblastoma tumor highlighted in red.Credits: Hellerhoff, Wikimedia Commons

Scientists in Toronto say that the healing process that follows brain damage can promote tumor growth when new cells created to replace cells lost due to damage are derailed by mutations. discovered. Brain damage can be anything from trauma to infections or strokes.

The findings were produced by a team of interdisciplinary researchers at the University of Toronto, Hospital for Sick Children (SickKids), and Princess Margaret Cancer Center. These teams also belong to the Pan-Canada Stand-up to Cancer Canada Dream Team, which has a common focus. A brain tumor known as glioblastoma.

“Our data suggest that changes in the correct mutations in certain cells in the brain can cause tumors due to injury,” said a senior scientist and director of neurosurgery. Dr. Peter Darks, Dream Team Leader, said. In the Sick Kids Development and Stem Cell Biology Program.

Gary Bader, a professor of molecular genetics at the Donnelly Cell and Biomolecules Research Center at the University of Toronto’s Medical Sciences Building, and Dr. Trevor Pew, a senior scientist at Princess Margaret, also led the study published today. .. Nature Cancer..

The findings may lead to new treatments for patients with glioblastoma, who have a life expectancy of 15 months after diagnosis and currently have limited treatment options.

“Glioblastoma can be thought of as a wound that doesn’t stop healing,” says Dirks. “I’m excited that this teaches us how cancer develops and grows, and it opens up entirely new ideas for treatment by focusing on injury and inflammatory responses.”

Researchers have applied the latest single-cell RNA sequencing and machine learning techniques to map the molecular composition of glioblastoma stem cells (GSCs). This has previously shown that the Dirks team is responsible for the development and recurrence of tumors after treatment.

They have discovered a new subpopulation of GSC that has the molecular characteristics of inflammation and is mixed with other cancer stem cells in the patient’s tumor. In some glioblastomas, when the normal tissue healing process, which produces new cells to replace the cells lost due to damage, is derailed by mutation, perhaps years before the patient becomes symptomatic. It suggests that it begins to form in.

Studies have shown that when mutant cells are involved in wound healing, they can’t stop growth because they break normal controls and promote tumor growth.

“The goal is to identify drugs that kill glioblastoma stem cells,” says graduate student Owen Whitley, who helped analyze the computational data. Target them more effectively. “

The team collected GSCs from the tumors of 26 patients and expanded them in the lab to obtain a sufficient number of these rare cells for analysis. Approximately 70,000 cells were analyzed by a single-cell RNA sequence that detects which genes are turned on in individual cells, led by Laura Richards, a graduate student in Pew’s lab. ..

The data confirmed widespread disease heterogeneity. That is, each tumor contains multiple subpopulations of cancer stem cells that are molecularly different, and existing treatments cannot wipe out all the different subclones, which can lead to recurrence.

A closer look reveals that each tumor is in one of two different molecular states called “development” and “damage response”, or somewhere in the gradient between the two.

The developmental state is characteristic of glioblastoma stem cells and resembles that of stem cells that are rapidly dividing in the prenatally growing brain.

But the second condition was a surprise. Researchers have named it the “injury response” because it showed the immune pathways that indicate the wound healing process and the up-regulation of inflammatory markers such as interferon and TNFalpha.

These immune signatures were acquired only thanks to new single cell technology, after being overlooked by older methods of bulk cell measurement.

Meanwhile, an experiment led by Stephen Angers’ lab at Lesliedan Pharmacy confirmed that the two states were vulnerable to different types of gene knockout and were not previously considered glioblastoma. A band of therapeutic targets associated with inflammation has been identified.

Finally, the relative mixture of the two conditions was found to be patient-specific. This means that each tumor is biased towards either the developmental edge of the gradient or the injury reaction edge. Researchers are now aiming to turn these biases into adjusted treatments.

“We are currently looking for drugs that are effective in many areas of this gradient,” says Pew, who is also the director of genomics at the Ontario Cancer Institute. “There is a real opportunity for precision medicine here. Designing a drug cocktail that can analyze a patient’s tumor at the single-cell level and extract multiple cancer stem cell subclones at the same time.”

Disassembling the complexity of glioblastoma reveals its developmental pattern

For more information:
The gradient transcriptional state of the developmental and injury response defines the functional fragility that underpins the heterogeneity of glioblastoma. Nature Cancer (2021). DOI: 10.1038 / s43018-020-00154-9, / articles / s43018-020-00154-9

Courtesy of the University of Toronto

Quote: Brain tumors associated with tissue healing (January 4, 2021) were obtained from on January 4, 2021. Was

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