Glioblastoma erodes skull and disrupts immune system, study reveals
Researchers have discovered that glioblastoma, the most aggressive form of brain cancer, extends beyond the brain by eroding the skull and altering the immune cells in skull marrow. This interaction fuels the cancer's progression and explains why current treatments often fail. The findings, published in Nature Neuroscience, suggest new strategies targeting both brain and bone.
Scientists at Montefiore Einstein Comprehensive Cancer Center and Albert Einstein College of Medicine found that glioblastoma erodes skull bones, particularly along the sutures where bones fuse, and changes the composition of skull marrow to favor pro-inflammatory immune cells. Using advanced imaging on mice with two types of glioblastomas, the team observed increased skull thinning and widened channels connecting the skull marrow to the brain. These channels allow inflammatory neutrophils and monocytes to enter the tumor, making it more aggressive, while reducing antibody-producing B cells.
"The skull-to-brain channels allow an influx of these numerous pro-inflammatory cells from the skull marrow to the tumor, rendering the glioblastoma increasingly aggressive and, all too often, untreatable," said study co-author E. Richard Stanley, Ph.D., professor of developmental and molecular biology at Einstein.
The research, prompted by recent studies on skull-brain connections, used single-cell RNA sequencing to show a near doubling of inflammatory neutrophils in skull marrow, contrasting with suppressed immune cell production in femur marrow. Computerized-tomography images from human patients confirmed skull thinning in areas matching the mouse models. Such erosions appear unique to glioblastoma and other malignant intracranial tumors, not seen in strokes or other cancers.
Testing anti-osteoporosis drugs like zoledronic acid and denosumab, which halt bone loss, revealed mixed results: they stopped erosion but zoledronic acid accelerated one tumor type, and both blocked the benefits of anti-PD-L1 immunotherapy. "Our discovery that this notoriously hard-to-treat brain cancer interacts with the body's immune system may help explain why current therapies have failed, and it will hopefully lead to better treatment strategies," said corresponding author Jinan Behnan, Ph.D.
According to the National Cancer Institute, about 15,000 people are diagnosed with glioblastoma annually, with a median survival of 15 months under standard surgery, chemotherapy, and radiation. The study reframes glioblastoma as a systemic disease, calling for therapies that balance skull marrow immune cells.