Brain tumors induce widespread disruption of calvarial bone and alteration of skull marrow immune landscape
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.
Authors
- Raoul Kuiper (ORCID: https://orcid.org/0000-0001-5645-2389)
- David Fooksman (ORCID: https://orcid.org/0000-0001-7601-4255)
- Nathaniel J. Killian (ORCID: https://orcid.org/0000-0002-4546-0516)
- Erika Yamashita (ORCID: https://orcid.org/0000-0002-3973-9529)
- Benjamin Himes (ORCID: https://orcid.org/0000-0001-5420-068X)
- Qinyong Ye (ORCID: https://orcid.org/0000-0002-0021-0257)
- Jinghang Zhang (ORCID: https://orcid.org/0000-0003-1436-6460)
- Alexander F. Fiedler (ORCID: https://orcid.org/0000-0003-3258-5640)
- Yutaka Uchida (ORCID: https://orcid.org/0000-0003-4899-2128)
- Winson S. Ho (ORCID: https://orcid.org/0000-0001-5943-1436)
- Kostantin Dobrenis (ORCID: https://orcid.org/0000-0001-7495-2475)
- Biljana Stangeland (ORCID: https://orcid.org/0000-0002-1723-9742)
- Emad N. Eskandar (ORCID: https://orcid.org/0000-0003-4743-2938)
- Gregory M. Palmer
- Masaru Ishii (ORCID: https://orcid.org/0000-0002-4215-007X)
- Robert A. Harris (ORCID: https://orcid.org/0000-0003-4990-509X)
- Jinan Behnan (ORCID: https://orcid.org/0000-0001-5780-0971)
- Kevin Fisher
- E. Richard Stanley (ORCID: https://orcid.org/0000-0002-2910-2065)
- Rachel L. Welch (ORCID: https://orcid.org/0000-0003-4698-2372)
- Derek M. Huffman (ORCID: https://orcid.org/0000-0002-2292-3717)
- Sayied Abdol Mohieb Hosainey (ORCID: https://orcid.org/0000-0002-4287-4545)
- Wade Koba (ORCID: https://orcid.org/0000-0002-6015-8382)
- Olivia R. Lu
- Zhigang Wu (ORCID: https://orcid.org/0000-0002-6782-9249)
- Abhishek Dubey (ORCID: https://orcid.org/0000-0002-1037-0174)
- D. John M. Reynolds
- Imane Abbas (ORCID: https://orcid.org/0009-0007-1443-9523)
Institutions
- Albert Einstein College of Medicine (US)
- Montefiore Medical Center (US)
- University of California, San Francisco (US)
- University Hospital Southampton NHS Foundation Trust (GB)
- Karolinska Institutet (SE)
- German Rheumatism Research Centre (DE)
- Duke Medical Center (US)
- Neurological Surgery (US)
- Freie Universität Berlin (DE)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1038/s41593-025-02064-4
- Citations
- 1
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- National Institutes of Health
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- H2020 Marie Skłodowska-Curie Actions