Findings by a team of Israeli and American scientists researching the structure and behavior of brain tumors may open new avenues of treatment for particularly aggressive brain tumors.

Researchers from the Weizmann Institute in Rehovot and Massachusetts General Hospital in Boston revealed that the orderly, layered structure of more aggressive tumors may make them more resistant to treatments. Certain layers, particularly those deep within the tumor, may be less accessible to drugs and immune cells, which could explain why current therapies are often ineffective.

By mapping how tumors arrange themselves and which cells are in each layer, researchers can potentially develop more targeted therapies.

The scientists examined two types of tumors found in the brain that arise from glial cells, which normally help neurons efficiently send electrical signals across the body’s nervous system. The two tumors — known as glioblastoma and glioma — are notoriously aggressive and difficult to treat. Success rates for treating these types of cancer have remained low, partly because scientists still have much to learn about the identity and behavior of the different cell groups that make up these tumors.

However, the advent of single-cell sequencing technology allowed researchers led by Dr. Itay Tirosh of the Weizmann Institute, in collaboration with Professor Mario Soba’s group at Massachusetts General Hospital, to analyze thousands of cells within a tumor in great detail, understand the genes they express, and classify them into distinct groups.

The findings were recently published in the peer-reviewed Cell journal.

Some glioma-type tumors have mutations in the IDH (isocitrate dehydrogenase) gene, which generally leads to less aggressive behavior and a better prognosis. On the other hand, glioblastoma-type tumors lack that mutation.

In earlier work, Tirosh’s team had already identified distinct groups of cells in both tumor types using single-cell genetic sequencing. These groups exhibited unique gene programs dictating the cancer cells’ biological state. Some of the cells even mimicked normal brain cells, further complicating the tumor’s behavior and its interaction with surrounding healthy tissue.

In the current study, the scientists went a step further.

By combining single-cell sequencing with spatial mapping techniques to identify which genes are expressed in various regions of the tumor, the researchers were able to create detailed maps of how glioblastoma and glioma tumors are organized within the brain. Tissue samples from 19 patients (13 with glioblastoma and six with IDH-mutant glioma) revealed a complex and dynamic tumor architecture.

One of the key findings was that the different groups of cells within gliomas are not randomly distributed throughout the tumor but instead cluster in specific microenvironments. These microenvironments are not entirely homogeneous, as different cell groups tend to neighbor each other.

For instance, progenitor cells — those that can give rise to various cell types — were often found near endothelial cells, which form the lining of blood vessels. This pairing mirrors a relationship seen in healthy tissue, where endothelial cells secrete substances that support the survival of progenitor cells.

The researchers also discovered that tumors form distinct layers, each with a unique cellular composition.

The tumor’s core, they found, consists of dead oxygen-starved cells. Surrounding it are layers of connective tissue-like cells, immune cells, and blood vessels. The outer layers are where tumor cells begin to mimic normal brain tissue, with groups of progenitor and support cells. The outermost layer contains healthy brain tissue into which the tumor invades.

This layered structure appears to be driven by a lack of oxygen, which intensifies as the tumor grows, the researchers said. Tumors with a lower grade of severity, such as IDH-mutant gliomas, tend to have a more chaotic and irregular structure compared to higher-grade, more aggressive tumors like glioblastomas. The orderly, layered organization of aggressive tumors is believed to make them more resistant to treatment. The distinct layers may form protective barriers, shielding certain cells from drugs and immune system attacks.

“We discovered that the orderly spatial structure characterizes aggressive tumors of a higher degree of severity,” said Tirosh. “The oxygen level in the tumor’s environment affects the gene program expressed by the cancer cells and their state. These distinct layers can be less accessible to drugs and immune cells, potentially making the tumor more resistant to treatment.”

With a more precise understanding of the cellular makeup and structure of brain tumors, doctors could tailor treatments to the specific characteristics of a patient’s tumor, moving toward more personalized and effective cancer therapies. Treatments could be designed to break down the tumor’s defenses, penetrate the deeper layers, or disrupt the interactions between different cell groups that help the tumor survive and grow.