Study reveals complex genetics behind the survival and growth of brain tumors

New insights on the genetic factors that enable brain tumors to survive and grow, just published in the journal Nature Communications, could pave the way for a more targeted approach to treating brain cancer.

Gliomas, brain tumors that originate from glial cells which provide support for neurons, are one of the most lethal forms of cancer with relatively few effective treatment options available. Halting the growth of these tumors has proven challenging because a single tumor can contain many different types of cells and can adapt quickly when treatments are administered.

Advanced technology and a clever new approach have allowed a research team from the Keck School of Medicine of USC and City of Hope, a national cancer research and treatment organization, to uncover details about gliomas, including the most aggressive form of brain cancer—glioblastoma—that may ultimately inform personalized therapies.

“These tools can help us understand the relationship between a tumor and its surrounding environment in a way we’ve never been able to study it before,” said corresponding author Gabriel Zada, MD, a professor of neurological surgery and physiology and neuroscience and director of the USC Brain Tumor Center.

The preclinical study, funded in part by the National Institutes of Health, used DNA and RNA sequencing, as well a cutting-edge method known as spatial transcriptomics, to analyze key genes in brain cancer tumors and their immediate surroundings, known as the tumor microenvironment. Spatial transcriptomics is a new method that allows researchers to view genetic information “in situ”—in its natural position—that can reveal key insights about biological processes such as how cancer spreads.

One notable finding from the study: Gliomas often house several “subclones” of tumors cells, each with slightly different DNA expression, making it easier for cancer cells to evade treatment that targets a specific cell type.

“Moving towards precision medicine, this is very important data that can ultimately prepare us to treat patients more effectively,” Zada said.

Why brain tumors resist treatment

To gain insight on a range of gliomas, the researchers analyzed tissue samples taken from 11 separate patients during brain surgery. With each sample, they conducted complementary DNA sequencing, RNA sequencing and spatial transcriptomic analysis of both tumor cells and the surrounding microenvironment.

Spatial transcriptomic analysis, done in collaboration with biotechnology company 10x Genomics, provided the researchers with a highly-detailed picture—almost down to the individual cell—of how gliomas invade healthy tissue in a patient’s brain, and what genes may mediate this process.

The samples were found to contain several distinct types of tumor cells, known as subclones, each with its own DNA signature. Understanding that variation within brain tumors, especially treatment-resistant glioblastoma, is a critical part of learning how to shrink them, Zada said.

“Glioblastoma is essentially several tumors mixed together. There are many different genetic patterns in any single ‘tumor,’” he said. “That’s part of what makes it tough to treat, because if you just target one cell type, the others survive.”

The researchers also saw an increase in extrachromosomal DNA, which are pieces of DNA found outside their standard location in the nucleus of cells. These DNA fragments can promote tumor growth by quickly upregulating genes associated with cancer, including the EGFR gene, which has been closely linked with glioblastoma and other cancers.

Using six additional tumor samples, Zada and his team then validated the findings, suggesting that the insights are likely to apply more broadly across glioma cases.

“By uniquely combining our expertise in pathology, neurosurgery, and advanced genomics with the power of AI and machine learning, we have uncovered new insights into how gliomas evade treatment, paving the way for new avenues for improvement outcomes and treatments in this devastating disease,” said David Craig, Ph.D., professor and chair of the Department of Integrative Translational Sciences at City of Hope and co-corresponding author of the new study.

The road to personalized medicine

The study paints a detailed picture of how genetic changes within brain tumors fuel their growth and survival, setting the stage for future studies that delve deeper into the exact biological mechanisms at play. It also suggests how personalized medicine may be effective against gliomas, for example by delivering several different treatments to target each subclone within a given tumor.

A long-term goal of the Keck School of Medicine-City of Hope group is to use spatial transcriptomics to diagnose and personalize treatment for gliomas. First, the researchers will validate their findings in a larger group of patients using the advanced research pipeline at the USC Brain Tumor Center.

About this research

In addition to Zada, the study’s other authors are Michelle G. Webb, Frances Chow, Carmel G. McCullough, Bohan Zhang, Rania Bassiouni, Normal E. Garrett III and Kyle Hurth from the Department of Translational Genomics, Keck School of Medicine of USC, University of Southern California; John D. Carpten and David W. Craig from the Keck School of Medicine of USC, University of Southern California and the Department of Integrated Translational Sciences, City of Hope; and John Lee from the Department of Integrated Translational Sciences, City of Hope.

This work was supported by the National Center for Advancing Translational Science of the National Institutes of Health [KL2TR001854].