Brain Organoids Reveal Glioblastoma Origins

By Nicholas Weiler | | January 03, 2020

Glioblastoma cells (green) invade a brain organoid grown from human stem cells (blue).

Glioblastomas are the most aggressive form of brain cancer — they grow and spread rapidly through the brain and are virtually impossible to eradicate, typically leading to death within one or two years of diagnosis. Scientists are constantly seeking more powerful targeted therapies, but so far without success — in part because glioblastomas are challenging to study in a laboratory setting. 

“Glioblastomas are aggressive and tenacious in patients, but have always been very difficult to keep alive in the lab,” said UC San Francisco postdoctoral researcher Aparna Bhaduri, PhD. “In previous attempts to study glioblastomas in mice, only 5 to 10 percent of human tumors survive transplantation into the animals, making us suspect that these tumors may differ in important ways from the ones that don’t survive.”

Now Bhaduri and Elizabeth Di Lullo, PhD, a fellow postdoctoral researcher in the laboratory of Arnold Kriegstein, MD, PhD, at the UCSF Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, have for the first time succeeded in keeping a diverse array of glioblastomas alive in the lab using brain organoids — balls of simple brain tissue grown from human stem cells.

“The tumors take to our organoid models nearly 100 percent of the time, meaning that we can finally study the full spectrum of glioblastomas in the lab,” Di Lullo said.

In a study published January 2, 2020 in Cell Stem Cell, Bhaduri, Di Lullo, and colleagues first created an atlas of glioblastomas taken from surgical treatment of human patients, cataloguing dozens of distinct cell types and these cells’ expression of distinctive patterns of genes. They then used organoids grown from human stem cells to model how these genetically identified cancer cell types behave in human brain tissue.

They discovered that glioblastomas do not appear to originate from a single cell type — what other researchers have called a “glioblastoma stem cell” — but instead arise from multiple kinds of seed cells, including one that looks and behaves very much like a neuronal stem cell Kriegstein’s lab discovered a decade ago, called an outer radial glia (oRG) cell.