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The healing process that follows a brain injury could stimulate tumor growth when new cells generated to replace those lost to the injury are derailed by mutations, scientists in Toronto have found.
Brain injury can range from trauma to 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 part of the Pan-Canadian Dream Team Stand Up To Cancer Canada who focuses on a brain cancer called glioblastoma.
“Our data suggests that the right mutational change in particular brain cells could be altered by injury to give rise to a tumor,” said Dr Peter Dirks, leader of the dream team who is the head of the division. of Neurosurgery and Senior Scientist. in the Developmental and Stem Cell Biology program at SickKids.
Gary Bader, professor of molecular genetics at the Donnelly Center for Cellular and Biomolecular Research at U of T’s Temerty School of Medicine and Dr Trevor Pugh, senior scientist at Princess Margaret, also led the research which was published today ‘hui in the journal Cancer de la nature.
The findings could lead to a new treatment for patients with glioblastoma who currently have limited treatment options with an average lifespan of 15 months after diagnosis.
“Glioblastoma can be thought of as a wound that keeps healing. We are excited about what this teaches us about the origin and growth of cancer and it opens up entirely new ideas for treatment focusing on the response to injury and inflammation, ”Dirks said.
Researchers applied the latest single-cell RNA sequencing and machine learning technologies to map the molecular composition of glioblastoma stem cells (GSCs), which Dirks’ team has previously shown to be responsible for initiating and tumor recurrence after treatment.
They discovered new subpopulations of GSCs that carry the molecular characteristics of inflammation and that are mixed with other cancer stem cells inside patients’ tumors.
This suggests that some glioblastomas begin to form when the normal tissue healing process, which generates new cells to replace those lost as a result of injury, is derailed by mutations, perhaps even several years before patients fail. become symptomatic, Dirks said.
Once a mutant cell engages in wound healing, it cannot stop multiplying because normal controls are broken and this stimulates tumor growth, according to the study.
“The goal is to identify a drug that will kill glioblastoma stem cells,” says Bader, whose graduate student Owen Whitley helped analyze the computer data. “But first we had to understand the molecular nature of these cells so that we could target them more effectively. “
The team collected GSCs from 26 patient tumors and developed them in the laboratory to obtain sufficient numbers of these rare cells for analysis. Almost 70,000 cells have been analyzed by single-cell RNA sequencing that detects which genes are turned on in individual cells, an effort led by Laura Richards, a graduate student of Pugh’s lab.
The data confirmed a great heterogeneity of the disease, which means that each tumor contains several molecularly distinct cancer stem cell subpopulations, making recurrence likely because existing therapy cannot eliminate all of the different subclones.
Closer examination revealed that each tumor has one of two distinct molecular states – called “developmental” and “injury response” – or somewhere on a gradient between the two.
The developmental state is a hallmark of glioblastoma stem cells and resembles that of rapidly dividing stem cells in the growing brain before birth.
But the second state was a surprise. The researchers called it the “injury response” because it showed upregulation of immune pathways and markers of inflammation, such as interferon and TNFalpha, which indicate wound healing processes.
These immune signatures were only captured using new single-cell technology after being missed by older methods of measuring bulk cells.
Meanwhile, experiments conducted by Stéphane Angers’ lab at Leslie Dan’s Faculty of Pharmacy established that the two states are vulnerable to different types of gene knockouts, revealing a host of inflammation-related therapeutic targets that had not previously been considered for glioblastoma.
Finally, the relative mixture of the two states was found to be patient specific, meaning that each tumor was biased either towards development or towards the injury response end of the gradient. Researchers are now looking to target these biases for tailor-made therapies.
“We’re now looking for drugs that are effective at different points of this gradient,” said Pugh, also director of genomics at the Ontario Institute for Cancer Research.
“There is a real opportunity here for precision medicine: to dissect patients’ tumors at the single cell level and design a drug cocktail that can eliminate more than one cancer stem cell subclone at the same time,” Pugh added.
(This story was posted from an agency feed thread with no text editing)
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