Highlights in Cancer Research: December 2024

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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8. Macrophage-mediated myelin recycling fuels brain cancer malignancy

Kloosterman, D.J., Erbani, J. et al. Cell. 187 (19): 5336-5356.e30 (2024).
doi: 10.1016/j.cell.2024.07.030.

Summary of the findings

Glioblastoma is the most common and aggressive form of primary brain cancer. Despite significant advances in our understanding of this disease, the standard of care has remained unchanged. The lack of efficacy of novel therapies in glioblastoma, such as immunotherapies, is partly attributed to the accumulation of immunosuppressive, tumor-associated macrophages (TAMs) within the tumor microenvironment. However, the high macrophage heterogeneity displayed in glioblastoma challenges a “one-size-fits-all” therapeutic approach, calling for an in-depth appreciation of their immense plasticity.

In this study, we employ a multi-omics approach to resolve the heterogeneity and spatial diversity of TAMs, revealing a subset of pro-tumorigenic macrophages characterized by accumulation of lipids droplets. Mechanistically, cholesterol-rich myelin debris engulfment by TAMs drives the formation of lipid-laden macrophages (LLMs) which display immunosuppressive features. Importantly, LLMs are enriched in the most aggressive, mesenchymal subtype of glioblastoma. Mesenchymal cancer cells prime the formation of LLMs and co-localize with these cells to scavenge the myelin-derived lipids effluxed by LLMs to fuel cancer outgrowth. This study highlights how brain tumors co-opt the homeostatic, myelin recycling functions of macrophages to support malignancy. Altogether, we shed light onto the regulation of macrophage heterogeneity and advance potential new avenues for subset-specific targeting of macrophages in glioblastoma.

Following engulfment of cholesterol-rich myelin debris through the lipid receptor CD36, tumor-associated macrophages acquire a lipid-laden phenotype in the glioblastoma tumor microenvironment. Lipid accumulation leads to Dhcr24 and lipid biosynthesis downregulation in lipid-laden macrophages (LLMs), which results in the accumulation of desmosterol. Following desmosterol-mediated LXR activation, LLMs downregulate inflammatory responses and upregulate the lipid exporters ABCA1/ABCG1 to promote cholesterol efflux. Mesenchymal (MES)-like glioblastoma cells scavenge LLM-derived lipids to fuel proliferation and fitness. Moreover, macrophage-mediated myelin uptake protects glioblastoma cancer cells from the myelin lipotoxic effect, altogether promoting glioblastoma malignancy.

Future impact

This study identifies a novel mechanism through which immunosuppressive, lipid-laden macrophages are generated and fuel glioblastoma cell growth through transfer of myelin-derived cholesterol. The discovery of LLMs and the pro-tumorigenic functions they exert in the glioblastoma TME highlights the currently understudied aspects of metabolic rewiring as a central co-evolution feature in brain cancers, opening novel avenues for therapeutic interventions in this disease. Additionally, LLMs could represent novel biomarkers able to predict glioblastoma subtype composition, prognosis and response to immunotherapy.