Macrophage-mediated myelin recycling fuels brain cancer malignancy
Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.
Authors
- Anita E. Grootemaat (ORCID: https://orcid.org/0000-0002-4209-8232)
- Dieta Brandsma (ORCID: https://orcid.org/0000-0001-7998-9904)
- B. Ewa Snaar‐Jagalska (ORCID: https://orcid.org/0000-0002-3772-047X)
- Gabriel Forn‐Cuní (ORCID: https://orcid.org/0000-0001-5976-4759)
- Brian Ruffell (ORCID: https://orcid.org/0000-0002-3846-6872)
- Kevin Petrecca (ORCID: https://orcid.org/0000-0002-8140-6402)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Shanna M. Handgraaf
- Nicole N. van der Wel (ORCID: https://orcid.org/0000-0001-6392-3417)
- Ning Qing Liu (ORCID: https://orcid.org/0000-0002-3151-638X)
- Johanna Erbani (ORCID: https://orcid.org/0000-0001-8356-9152)
- Marjolijn Mertz (ORCID: https://orcid.org/0000-0002-9188-3579)
- Masami Ando‐Kuri (ORCID: https://orcid.org/0000-0002-7594-3359)
- Leila Akkari (ORCID: https://orcid.org/0000-0001-5479-641X)
- Luuk Reinalda
- Elzo de Wit (ORCID: https://orcid.org/0000-0003-2883-1415)
- Alexander Kros (ORCID: https://orcid.org/0000-0002-3983-3048)
- Elena Sánchez‐López (ORCID: https://orcid.org/0000-0001-8546-766X)
- Daan J. Kloosterman (ORCID: https://orcid.org/0000-0003-1082-070X)
- Menno Boon
- Bauke Fontein
- Marja Nieuwland
- Sander I. van Kasteren (ORCID: https://orcid.org/0000-0003-3733-818X)
- Martina Farber
Institutions
- Leiden University (NL)
- Leiden University Medical Center (NL)
- McGill University Health Centre (CA)
- The Netherlands Cancer Institute (NL)
- Moffitt Cancer Center (US)
- Netherlands Metabolomics Centre (NL)
- Oncode Institute (NL)
- Cancer Genomics Centre (NL)
- Erasmus MC Cancer Institute (NL)
Publication Details
- Journal
- Cell
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1016/j.cell.2024.07.030
- Citations
- 156
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 37.52
Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Oncode Institute