Brain cancer that eats the skull stuns scientists

"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.

The NCI reports that around 15,000 people in the United States are diagnosed with glioblastoma each year. For those receiving the current standard of care, which includes surgery, chemotherapy, and radiation, the median survival time is about 15 months.

A Matter of Marrow

Like other bones in the body, the skull contains marrow that produces immune cells and other blood cells. Dr. Behnan's team was inspired by recent discoveries showing that extremely thin channels connect the skull to the brain, enabling the exchange of molecules and immune cells between the two.

Using advanced imaging tools, the researchers studied mice that developed two types of glioblastoma. They found that the cancer caused erosion of skull bones, particularly along the sutures where the bones fuse. This type of bone loss appeared to be specific to glioblastoma and other aggressive brain tumors; it did not occur in mice that experienced strokes, other forms of brain injury, or cancers elsewhere in the body. CT scans of human patients with glioblastoma revealed similar reductions in skull thickness in the same regions observed in mice.

In mice, the erosion of skull bone increased both the number and size of the channels linking the skull and brain. The scientists proposed that these enlarged channels might allow the tumor to send molecular signals into the skull marrow, altering its immune environment.

A Tilt Toward 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.