The healing process that follows a brain injury could stimulate tumor growth when new cells are formed to destroy those lost to the injury by mutations, Toronto scientists have found.
A brain injury can be anything from trauma to an infection or stroke.
The findings were made by an interdisciplinary team of researchers from the University of Toronto, the Hospital for Sick Children (SickKids) and the Princess Margaret Cancer Center who are also on the Canadian Stand Up to Cancer Dream Team targets a common brain cancer called glioblastoma.
“Our data suggest that the right mutational change in specific cells in the brain could be altered by injury to cause tumors,” said Dr. Peter Dirks, Dream Team leader who is Head of the Department of Neurururgery and Senior in SickKids’ Developmental and Gas Cell Biology program.
The research was also led by Gary Bader, professor of molecular genetics at the Donnelly Center for Cellular and Biomolecular Research at the Temerty U of T Faculty of Medicine and Dr Trevor Pugh, Princess Margaret’s Senior Specialist. published today in the journal Nature Cancer.
The findings could lead to a new treatment for glioblastoma patients who currently have limited treatment options with an average life of 15 months after diagnosis.
“Glioblastoma can be thought of as an injury that never stops. We are excited about what this tells us about how cancer emerges and grows and it opens up completely new ideas about treatment by focusing on the response to injuries and inflammation, ”he said. Dirks.
The researchers used the latest single-cell RNA sequencing technologies and learned machines to make up molecular uptake of the glioblastoma stem cells (GSCs), previously demonstrated by Dirks’ team responsible for tumor initiation and subsequent recurrence. treatment.
They found new subtypes of GSCs that carry molecular signs of inflammation and that come with other cancer stem cells within patient tumors.
He suggests that some glioblastomas begin to form when the normal healing process, which generates new cells to replace those lost by injury, is removed by mutations, perhaps even several years before patients become symptoms, Dirks said.
Once a mutant cell is involved in wound healing, it cannot stop proliferation because the normal controls are broken and this stimulates tumor growth, according to the study.
“The goal is to identify a drug that kills the glioblastoma stem cells,” says Bader, who added graduate student Owen Whitley to the computer data analysis. “But first we needed to understand the molecular nature of these cells in order to would we be able to focus on them more effectively. ”
The GSCn team collected tumors from 26 patients and expanded them in the laboratory to obtain sufficient numbers of these rare cells for analysis. Nearly 70,000 cells were studied with single-cell RNA sequences that detect which genes are turned into individual cells, an effort led by Laura Richards, a graduate student in Pugh’s laboratory.
The data confirmed the heterogeneity of diseases, resulting in several subtypes of specific molecular cancer cells in each tumor, making recurrence likely by the fact that the existing treatment cannot eliminate the tumors. various sub-stones.
A closer look showed that each tumor has one of two distinct molecular states – known as “Supplementary” and “Injury Response” – or somewhere on the gradient between the two.
The developmental state is characteristic of the glioblastoma stem cells and is similar to the rapidly dividing stem cells in the pre-natal growing brain.
But the second state came as a surprise. The researchers described it as an “Injury Response” because it showed an increase in immune pathways and inflammation symptoms, such as interferon and TNFalpha, which are indicative of wound healing processes.
These protective names were built only thanks to the new single-cell technology after being lost by old methods for measuring large cells.
At the same time, laboratory-led experiments led by Stephane Angers at the Faculty of Pharmacy Leslie Dan established that both states are vulnerable to different types of gene mutation, revealing a number of therapeutic targets associated with undiagnosed inflammation. previously considered for glioblastoma.
Finally, it was found that the relative incomes of the two states were specifically for patients, meaning that each tumor was biased either toward the head of development or the end of the gradient injury. The researchers are now looking to target these biases for specific therapies.
“We are now looking for drugs that are effective at various points of this gradient,” said Pugh, who is also Director of Genomics at the Ontario Institute for Cancer Research.
“There is a real opportunity here for precision treatment – eradicating patient tumors at the single-cell stage and designing a drug cocktail that removes more than one sub-cell of cancer cells at the same time, ”Said Pugh.
(This story was published from a wire group group without text editing)
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