Tissue healing after brain injury could spur tumor growth
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The healing process that follows a brain injury could spur tumor growth when new cells generated to replace those lost to the injury are derailed by mutations, Toronto scientists have found. A brain injury can be anything from trauma to infection or stroke. The findings have been published today in the journal Nature Cancer.

"This data suggest that the right mutational change in particular cells in the brain could be modified by injury to give rise to a tumor," says researcher.

The findings could lead to new therapy for glioblastoma patients who currently have limited treatment options with an average lifespan of 15 months after diagnosis.

The researchers applied the latest single-cell RNA sequencing and machine learning technologies to map the molecular make-up of the glioblastoma stem cells (GSCs), which Dirks' team previously showed are responsible for tumor initiation and recurrence after treatment.

They found new subpopulations of GSCs which bear the molecular hallmarks of inflammation and which are comingled with other cancer stem cells inside patients' tumors. It suggests that some glioblastomas start to form when the normal tissue healing process, which generates new cells to replace those lost to injury, gets derailed by mutations, possibly even many years before patients become symptomatic, researchers said.

Once a mutant cell becomes engaged in wound healing, it cannot stop multiplying because the normal controls are broken and this spurs tumor growth, according to the study.

"The goal is to identify a drug that will kill the glioblastoma stem cells," says researcher "But we first needed to understand the molecular nature of these cells in order to be able to target them more effectively."

The team collected GSCs from 26 patients' tumors and expanded them in the lab to obtain sufficient numbers of these rare cells for analysis. Almost 70,000 cells were analyzed by single-cell RNA sequencing which detects what genes are switched on in individual cells.

The data confirmed extensive disease heterogeneity, meaning that each tumor contains multiple subpopulations of molecularly distinct cancer stem cells, making recurrence likely as existing therapy can't wipe out all the different subclones.

A closer look revealed that each tumor has either of the two distinct molecular states--termed "Developmental" and "Injury Response"-- or somewhere on a gradient between the two.

The developmental state is a hallmark of the glioblastoma stem cells and resembles that of the rapidly dividing stem cells in the growing brain before birth.

But the second state came as a surprise. The researchers termed it "Injury Response" because it showed an upregulation of immune pathways and inflammation markers, such as interferon and TNFalpha, which are indicative of wound healing processes.

These immune signatures were only picked up thanks to the new single-cell technology after being missed by older methods for bulk cell measurements.

Meanwhile, experiments established that the two states are vulnerable to different types of gene knock outs, revealing a swathe of therapeutic targets linked to inflammation that had not been previously considered for glioblastoma.

Finally, the relative comingling of the two states was found to be patient-specific, meaning that each tumor was biased either toward the developmental or the injury response end of the gradient. The researchers are now looking to target these biases for tailored therapies.

Source: https://www.nature.com/articles/s43018-020-00154-9
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