The origin of deadly brain cancer discovered

The finding could lead to potential therapies.

Glioblastoma is an aggressive type of cancer that can occur in the brain or spinal cord—glioblastoma forms from cells called astrocytes that support nerve cells.

Scientists from McGill University have identified the origin and a specific gene needed for tumor growth in Glioblastoma.

For the study, scientists assembled the most extensive collection of samples for this subgroup of Glioblastoma. They discovered cancer-causing mutations in a gene called PDGFRA. This gene drives cell division and growth when it is activated.

Dr. Carol Chen, a postdoctoral fellow, and Shriya Deshmukh, an MD-PhD candidate in the Jabado lab and the study’s co-first authors, said, “We investigated large public datasets of both children and adult patients in addition to those we had generated from patients’ samples in the lab and came to the same conclusion, PDGFRA was unduly activated in these tumors. This led us to suspect this kinase plays a major role in tumor formation.”

Using new technologies, scientists measured the levels of every gene in thousands of individual cells. They discovered that this brain tumor originates in a specific type of neuronal stem cell.

Selin Jessa, a Ph.D. student in the Kleinman lab and co-first author on this study, said, “We used single-cell analyses to create an atlas of the healthy developing brain, identifying hundreds of cell types and their traits.”

Dr. Kleinman said, “Since these brain tumors retain a memory, or footprint, of the cell in which they originated, we could then pinpoint the most similar cell type for these tumors in the atlas, in this case, inhibitory neuronal progenitors that arise during fetal development or after birth in specific structures of the developing brain.”

The PDGFRA gene is not usually activated n this neuronal stem cell population.

Djihad Hadjadj, a postdoctoral fellow in the Jabado lab and the study’s co-first author, said, “By using sequencing technologies that measure how a cell’s DNA is spatially organized in 3D. We found that exquisitely in this neuronal stem cell, the DNA has a unique structure in the 3D dimension that allows the PDGFRA gene to become activated where it shouldn’t be, ultimately leading to cancer.”

“Previously, this tumor type was classified as a “glioma” because, under the microscope, it resembles glial cells, one of the major cell types in the brain. Our work reveals that this is a case of mistaken identity. These tumors arise in a neuronal cell, not a glial cell.”

There are approved drugs used to target PDGFRA, inhibit its activity for other cancers for which mutations in this gene are responsible, such as gastrointestinal stromal tumors. This offers hope in finding targeted treatments for these groups of deadly brain tumors, note the analysts.

Drs. Jabado and Kleinman said“Our findings provide hope for improved care soon for this tumor entity as these exquisite vulnerabilities may pinpoint to treatments that would preferentially attack the ‘bad’ cells.”

“Stalled development is at the root of many of these cancers. The same strategy will prove important to unravel the origin, identify and exploit specific vulnerabilities, and orient future strategies for earlier detection in other brain tumor entities affecting children and young adults.”

Journal Reference:
  1. Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis,” by C. Chen, S. Deshmukh, S. Jessa, D. Hadjadj, C. Kleinman, N. Jabado, et al., was published in the journal Cell on December 10, 2020. DOI: 10.1016/j.cell.2020.11.012

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