A deadly brain cancer with systemic consequences
Glioblastoma, the deadliest form of brain cancer, is not contained to the brain alone. New research from Montefiore Einstein Comprehensive Cancer Center (MECCC) and the Albert Einstein College of Medicine shows the aggressive tumor also erodes the skull bone and reshapes the skull’s immune landscape. The findings, published in Nature Neuroscience, suggest that glioblastoma interacts with the body’s immune system in ways that may help explain why existing therapies—surgery, chemotherapy, and radiation—often fail to cure the disease.
Experts note that roughly 15,000 people are diagnosed with glioblastoma each year, and even with standard treatment, median survival remains around 15 months. The new work adds a critical dimension to how clinicians understand and approach this complex disease by highlighting peripheral sites—specifically the skull marrow—that participate in tumor dynamics.
The skull as a hidden immune hub
The skull contains marrow just like other bones, a site where immune and blood cells are produced. The investigators were motivated by recent discoveries of unusually thin channels linking the skull marrow to the brain, which could permit molecules and cells to move between these compartments. Using advanced imaging in mice with two glioblastoma models, the team observed skull bone erosion, particularly along sutures where skull plates meet. These erosions were not seen in strokes or other brain injuries, suggesting a glioblastoma-specific effect. In patients, CT scans revealed parallel areas of thinning, underscoring the relevance of the mouse findings to human disease.
Additionally, the team found that the tumor correlates with wider skull-to-bone channels, which they hypothesize serve as highways for signals from skull marrow to reach the tumor. This anatomical bridge potentially allows the cancer to reshape its immune environment from the skull end, altering how the immune system responds to the tumor.
Shifting immune landscapes in the skull marrow
Single-cell RNA sequencing revealed a dramatic reconfiguration of immune cells in the skull marrow during glioblastoma. The tumor pushes the marrow toward a pro-inflammatory state dominated by myeloid cells, nearly doubling inflammatory neutrophils, while drastically reducing several B cell types and other antibody-producing cells. As co-author E. Richard Stanley, Ph.D., described, the skull-to-brain channels enable a flood of these inflammatory cells from the skull marrow into the tumor, contributing to increased tumor aggression and, in many cases, treatment resistance.
These findings imply that therapies aimed at merely blocking skull-bone loss could inadvertently fuel tumor growth unless they are paired with strategies to restore immune balance. The researchers emphasize a two-pronged approach: dampen pro-inflammatory neutrophils and monocytes while boosting the production or function of T and B cells to re-create a more effective anti-tumor environment.
Toward a systemic view of glioblastoma therapy
The study also added a surprising twist: glioblastoma affects different marrow sites in distinct ways. While skull marrow ramps up inflammatory pathways, the femur marrow shows a contrasting response, with gene changes that suppress several immune-cell lineages. This tissue-specific response reinforces the idea that glioblastoma behaves as a systemic disease rather than a purely local brain tumor, prompting a broader view of how and where to target the cancer and its immune milieu.
What this means for patients and future research
By illuminating how glioblastoma interacts with skull bone and skull marrow, the work lays groundwork for new therapeutic strategies that go beyond local tumor removal. Future treatments might combine approaches to curb harmful inflammatory signaling with methods to bolster adaptive immunity, potentially improving responses to immunotherapies and standard care. The findings underscore the need for clinical trials that monitor skull marrow biology and its immune signals as part of personalized treatment plans for glioblastoma patients.
