Glioblastoma Cancer Cells ‘Starve’ Without Astrocyte Immunometabolic Support
By Brittany Wade
September 20, 2022 | Glioblastoma multiforme is an aggressive and malignant brain cancer with exceptionally high mortality rates. Patients often endure epileptic seizures, edema, and intracranial hypertension before succumbing to the disease.
Over the past few decades, there have been many attempts to develop an effective treatment. However, glioblastoma is pervasive and highly resistant to most therapies, with surgical interventions posing more risks than benefits.
Determined to investigate alternative strategies, a team of researchers at Tel Aviv University began looking for ways to alter the tumor microenvironment (TME). They reasoned that since glioblastoma cells remained unresponsive to traditional targeted therapies, transforming the tumor’s surrounding environment might make a significant therapeutic impact.
The researchers focused on astrocytes, star-shaped cells in the TME that, under healthy conditions, physically and metabolically support neurons in the brain and spinal cord. However, in the presence of a tumor, healthy astrocytes differentiate into tumor-associated astrocytes (TAAs), shifting their support in favor of cancer cells and providing a lifeline for tumor growth.
Published in Brain (DOI: 10.1093/brain/awac222), the team—led by Rita Perelroizen, a Ph.D. student, with supervision from Dr. Lior Mayo of the Shmunis School of Biomedicine and Cancer Research and the Sagol School of Neuroscience and Eytan Ruppin, United States National Institutes of Health professor—observed glioblastoma progression in mice after conducting two experiments. The first involved removing functioning TAAs from the TME. The second interrupted TAA immunometabolic contributions to cancer cells.
The team used genetic ablation to eliminate functioning TAAs in mice. This technique deleted genes associated with two TAA hallmarks contributing to disease: high glial fibrillary acidic protein (GFAP) production and excessive proliferation rates. GFAPs provide astrocytes with structural support to carry out their duties. Once the TAAs were suppressed, the team observed a significant halt in tumor progression and increased survival rates.
"In the absence of astrocytes, the tumor quickly disappeared, and in most cases, there was no relapse—indicating that the astrocytes are essential to tumor progression and survival," reported Mayo in a press release.
Astrocyte Immunometabolic Signaling
A portion of TAA tumor control exists in its ability to recruit and influence existing macrophages. Healthy macrophages are phagocytic immune cells that engulf pathogenic organisms. In contrast, tumor-associated macrophages (TAMs) adopt roles that support tumor growth in the wake of tumor- and astrocyte-driven modifications to their RNA. While the specifics of this process are still largely unknown, scientists report that high TAMs concentrations correlate with a lower likelihood of glioblastoma patient survival.
“Astrocytes can send signals that summon immune cells to places in the brain that need protection. In this study, we found that astrocytes continue to fulfill this role in the presence of glioblastoma tumors. However, we found that the astrocytes change the ability of recruited immune cells to attack the tumor both directly and indirectly, thereby protecting the tumor and facilitating its growth," said Mayo.
Another critical component of glioblastoma tumor growth is its dependence upon astrocyte cholesterol production. Mayo refers to astrocytes as “cholesterol factories” because they supply the brain with energy by manufacturing and releasing cholesterol. Since glioblastoma cells proliferate rapidly, they rely heavily on astrocytes to support their continued cholesterol consumption.
“We discovered that the astrocytes surrounding the tumor increase the production of cholesterol and supply it to the cancer cells. Therefore, we hypothesized that, because the tumor depends on this cholesterol as its main source of energy, eliminating this supply will starve the tumor," said Mayo.
When the team arrested astrocytic cholesterol expression by blocking a designated transporter (chemical shuttle), they again saw a marked regression in tumor growth and prolonged survival. Similar results were also demonstrated using RNA data analysis of the TME in human glioblastoma patients under the same conditions.
Aside from potentially devising a viable cure for one of the most lethal cancers, the team also walked away with a newfound appreciation for the blood-brain barrier. Traditionally, the blood-brain barrier—of which astrocytes comprise a sizable portion—protects the brain from harmful substances in the blood. Unfortunately, it also prevents many brain cancer treatments from accessing the brain. What was previously thought to be a hindrance to cancer therapy has proven to be a significant asset.
"This work sheds new light on the role of the blood-brain barrier in treating brain diseases. Our findings suggest that, at least in the specific case of glioblastoma, the blood-brain barrier may be beneficial to future treatments, as it generates a unique vulnerability—the tumor's dependence on brain-produced cholesterol. We think this weakness can translate into a unique therapeutic opportunity," adds Mayo.
The challenge now will be to duplicate these findings in humans and develop drugs targeting specific TAA and TAM mechanisms for a holistic approach. “We think that the conceptual breakthroughs provided by this study will accelerate success in the fight against glioblastoma. We hope that our findings will serve as a basis for the development of effective treatments for this deadly brain cancer and other types of brain tumors," said Mayo.
The team’s research offers a glimmer of hope in the fight against glioblastoma where, for decades, there had been none. While more studies are required to understand the intricacies of astrocyte immunometabolic control, the team hopes their research will be a launching pad for new, intelligent, and precise cancer therapies for glioblastoma and beyond.
