“Our discovery that this notoriously hard-to-treat brain cancer interacts with the body’s immune system may help explain why current therapies—all of them dealing with glioblastoma as a local disease—have failed, and it will hopefully lead to better treatment strategies,” said the paper’s corresponding author Jinan Behnan, Ph.D., assistant professor in the Leo M. Davidoff Department of Neurological Surgery and in the department of microbiology & immunology at Einstein, and a member of the National Cancer Institute (NCI)-designated MECCC.
According to the NCI, approximately 15,000 people are diagnosed with glioblastoma each year. The median survival of those who receive standard treatment of surgery, chemotherapy, and radiation is approximately 15 months.
A Matter of Marrow
As is true for many other bones, the skull contains marrow in which immune cells and other blood cells form. Dr. Behnan’s research on glioblastoma and the skull was prompted by recent studies revealing extremely thin channels that connect the skull with its underlying brain, allowing molecules and cells to travel between the skull’s marrow and the brain.
Dr. Behnan and colleagues used advanced imaging techniques on mice that developed two different types of glioblastomas. They found that the tumors caused skull bones to erode, especially along the sutures where skull bones fuse. Such erosions seem to be unique to glioblastoma and other malignant intracranial tumors, since they don’t occur with strokes, other types of brain damage, or even other systemic cancers. Computerized-tomography (CT) images of patients with glioblastoma revealed that decreases in skull thickness were present in the same anatomic areas as in mice.
The skull erosions in the mice were found to have increased the number and diameter of the skull-to-bone channels. The researchers hypothesized that these channels might allow the glioblastoma to transmit signals to the skull marrow that could profoundly change its immune landscape.
A Tilt Towards Inflammation
Using single-cell RNA sequencing, the researchers found that glioblastoma had dramatically shifted the skull marrow’s immune-cell balance in favor of pro-inflammatory myeloid cells—nearly doubling the levels of inflammatory neutrophils, while nearly eliminating several types of antibody-producing B cells as well as other 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. “This indicates the need for treatments that restore the normal balance of immune cells in the skull marrow of people with glioblastoma. One strategy would be suppressing the production of pro-inflammatory neutrophils and monocytes while at the same time restoring the production of T and B cells.”
Interestingly, and adding to evidence that glioblastoma is a systemic rather than local disease, the marrows of the skull and femur reacted differently to the cancer. Glioblastoma activated several genes in the skull marrow that boosted production of inflammatory immune cells; but in femur marrow, the cancer suppressed genes needed to produce several types of immune cells.
The researchers wondered if administering anti-osteoporosis drugs that prevent bone loss would affect skull-bone erosion, glioblastoma, or both. To find out, they gave mice with glioblastoma tumors two different drugs approved by the U.S. Food and Drug Administration for treating osteoporosis. Both drugs (zoledronic acid and denosumab) halted skull erosion—but one of them (zoledronic acid) also fueled tumor progression in one type of glioblastoma. Both drugs also blocked the beneficial effects of anti-PD-L1, an immunotherapy drug that boosts levels of tumor-fighting T cells.
The Nature Neuroscience paper is titled “Brain Tumors Induce Widespread disruption of Calvarial Bone and Alteration of Skull Marrow Immune Landscape.” Additional MECCC and Einstein authors include Abhishek Dubey, Biljana Stangeland, Imane Abbas, David Fooksman, Ph.D., Wade R. Koba, B.S., Jinghang Zhang, M.D., Benjamin T. Himes, Ph.D., Derek Huffman, Ph.D., Zhiping Wu, Rachel Welch, David Reynolds, B.S., Kostantin Dobrenis, Ph.D., Qinge Ye, Kevin Fisher, and Emad Eskandar, M.D. Other authors include Erika Yamashita, Yutaka Uchida and Masaru Ishii, at Osaka University, Osaka, Japan, Robert A. Harris at Karolinska Hospital Solna, Stockholm, Sweden, Gregory M Palmer at Duke University Medical Center, Durham, North Carolina, Olivia R. Lu and Winson S. Ho at University of California, San Francisco, CA, and Alexander F. Fiedler at German Rheumatism Research Center (DRFZ) and Freie Universität Berlin, Berlin, Germany.
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About Montefiore Einstein Comprehensive Cancer Center
Montefiore Einstein Comprehensive Cancer Center (MECCC) is a National Cancer Institute (NCI)-designated comprehensive cancer center and a national leader in cancer research and care located in the racially and ethnically diverse borough of the Bronx, N.Y. MECCC combines the exceptional science of Albert Einstein College of Medicine with the multidisciplinary and team-based approach to cancer clinical care at Montefiore Health System. Founded in 1971 and a NCI-designated cancer center since 1972, MECCC is redefining excellence in cancer research, clinical care, education and training, and community outreach and engagement. Its mission is to reduce the burden of cancer for all, especially people from historically underrepresented groups.
About Albert Einstein College of Medicine
Albert Einstein College of Medicine is one of the nation’s premier centers for research, medical education and clinical investigation. During the 2024-25 academic year, Einstein is home to 712 M.D. students, 226 Ph.D. students, 112 students in the combined M.D./Ph.D. program, and approximately 250 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2024, Einstein received more than $192 million in awards from the National Institutes of Health. This includes the funding of major research centers at Einstein in cancer, aging, intellectual development disorders, diabetes, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. For more information, please visit einsteinmed.edu, follow us on Twitter, Facebook, Instagram, LinkedIn, and view us on YouTube.
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