Scientists uncover glioblastoma's impact on skull and immune system

Good news! Cancer is history (soon)! However, treating glioblastoma may even be more complicated than before.

"... Further investigation of human brain scans found that skull thickness had been altered by the tumors, particularly where bones fuse. ...

The researchers found that, in the mice, the erosion of the skull increased the number and size of skull-to-bone channels present, which they believed could be allowing tumor cells to impact marrow, affecting the body's immune system. Through single-cell RNA sequencing, the team indeed saw that glioblastoma upended the skull bone marrow's environment – filling it with pro-inflammatory neutrophils while decimating cancer-fighting 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,” ..."

"Scientists ... have shown for the first time that glioblastoma—the deadliest form of brain cancer—affects not just the brain but also erodes the skull, alters the makeup of skull marrow, and interferes with the body’s immune response. Drugs intended to inhibit skull-bone loss made the cancer more aggressive ...

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. ..."

From the abstract:

"The skull marrow niche has recently been identified as a reservoir that supplies the brain with monocytes and neutrophils in the context of disease and injury, but its role in brain cancers remains unknown.

Here we show that glioblastoma, the most malignant type of brain tumor, induces calvarial bone abnormalities in murine models and patients with glioblastoma, altering osteoclast activities and increasing the number of skull channels in mice.

Single-cell RNA sequencing revealed glioblastoma-mediated alterations in the immune landscape of skull marrow and femoral bone marrow, including expansion of neutrophils and deterioration of various B cell subsets.

In vivo inhibition of bone resorption reduced bone abnormalities, but promoted tumor progression in mesenchymal subtype tumors.

This also abolished the survival benefit of the checkpoint inhibitor anti-PD-L1, by reducing activated T cell and increasing inflammatory neutrophil numbers. Together, these data provide insight into how brain tumors affect skull bone and the immune environment."

Scientists uncover glioblastoma's impact on skull "For the first time, scientists have detailed how a deadly brain cancer has a unique path of progression, aggressively eating away at the skull itself – and how drugs to impede this end up making it worse."

Glioblastomas Affect Much More Than Just the Brain (original news release) "Finding Links Between Tumors and Skull Bone Marrow Could Lead to New Treatment Strategies"

Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape (open access)

Fig. 1: GBM induces calvarial bone abnormality and OC activity in several anatomical regions of the calvarium delineating osteogenic edges adjacent to the skull sutures.