Increase in inflammatory factors, presumably in response to brain injury, in tumor-initiating cells.
If new cells created to replace those lost to injury are derailed by mutations, the healing process after brain injury could stimulate tumor development, Toronto scientists have found.
From trauma to illness to stroke, brain damage may be anything.
An interdisciplinary team of researchers from the University of Toronto, the Hospital for Sick Children (SickKids) and the Princess Margaret Cancer Centre, who also participated in the Canada Dream Team of the Pan-Canadian Stand Up To Cancer, focusing on a common brain cancer known as glioblastoma, provided the results.
“Our data suggest that the right mutational change in certain cells in the brain could be modified by injury to give rise to a tumor,” said Dr. Peter Dirks, leader of the Dream Team, who is head of the Department of Neurosurgery and a senior scientist in the SickKids Developmental and Stem Cell Biology Program.
Gary Bader, Professor of Molecular Genetics at the Donnelly Center for Cell and Biomolecular Science, Temerty Faculty of Medicine, University of Temerty, and Dr.
The research, which was published today in the Nature Cancer journal, was also led by Trevor Pugh, senior scientist at Princess Margaret.
The findings could lead to new treatment for patients with glioblastoma who currently have limited options for treatment and a mean life expectancy of 15 months after diagnosis.
“Glioblastoma can be thought of as a wound that never stops healing,” Dirks says. “We’re excited by what this tells us about how cancer develops and grows, and it opens up whole new ideas for treatment by focusing on the injury and inflammatory response.”
In order to map the molecular makeup of glioblastoma stem cells (GSCs), the researchers applied the new single-cell RNA sequencing and machine learning technologies, which Dirks’ team had previously shown to be responsible for tumorigenesis and post-treatment recurrence.
New subpopulations of GSCs that bear the molecular hallmarks of inflammation and are mixed in patient tumors with other cancer stem cells have been discovered.
This means that certain glioblastomas occur when mutations are derailed by the usual tissue healing process in which new cells are created to replace those lost to injury, probably even several years before patients become symptomatic, Dirks said.
Once a mutant cell interferes with wound healing, since normal controls are broken, it can not stop replicating and that drives tumor development, the study found.
“The goal is to identify a drug that kills glioblastoma stem cells,” says Bader, whose graduate student Owen Whitley contributed to the study of computational data, “But we first needed to understand the molecular nature of these cells so we could target them more effectively.”
From the tumors of 26 patients, the team obtained GSCs and extended them in the laboratory to obtain adequate numbers of these unusual cells for study.
Nearly 70,000 cells were analyzed using single-cell RNA sequencing, which decides which genes are turned on in individual cells, work led by Laura Richards, a graduate student in Pugh’s lab.
The data indicated a high degree of heterogeneity in the disease, indicating that each tumor comprises several subpopulations of stem cells of molecularly distinct cancer, rendering disease recurrence possible since all the separate subclones can not be eradicated by established therapy.
Closer inspection showed that each tumor has either either of two different molecular states called “Developmental” and “Injury Response” or a gradient between the two somewhere.
The developmental condition is a characteristic of the stem cells of glioblastoma and resembles that of rapidly dividing stem cells prior to birth in the developing brain.
The second condition, however, came as a surprise.
The researchers named it Injury Response because it demonstrated upregulation of immune pathways and inflammatory markers that suggest wound healing processes, such as interferon and TNFalpha.
These immune signatures were found only after older methods of measuring mass cells were skipped, thanks to modern single-cell technology.
Meanwhile, studies conducted at the Leslie Dan Faculty of Pharmacy by Stephane Angers’ lab found that unteteing of the two states was normal.