Macrophage-mediated myelin recycling fuels brain cancer malignancy.

in Cell by Daan J Kloosterman, Johanna Erbani, Menno Boon, Martina Farber, Shanna M Handgraaf, Masami Ando-Kuri, Elena Sánchez-López, Bauke Fontein, Marjolijn Mertz, Marja Nieuwland, Ning Qing Liu, Gabriel Forn-Cuni, Nicole N van der Wel, Anita E Grootemaat, Luuk Reinalda, Sander I van Kasteren, Elzo de Wit, Brian Ruffell, Ewa Snaar-Jagalska, Kevin Petrecca, Dieta Brandsma, Alexander Kros, Martin Giera, Leila Akkari

TLDR

  • The study investigates how glioblastoma, a type of brain tumor, gets its energy. Glioblastoma grows in an environment where it can't make its own food, so it relies on the help of other cells in its surroundings, called the tumor microenvironment (TME). The study used single-cell and multi-omics analyses to look at the TME and identify a type of cell called a tumor-associated macrophage (TAM) that helps glioblastoma get its energy. These TAMs are called lipid-laden macrophages (LLMs) because they accumulate cholesterol. LLMs are also epigenetically rewired, meaning their genes are changed in a way that makes them work differently, and they display immunosuppressive features, meaning they help glioblastoma grow by suppressing the immune system. LLMs are also enriched in the aggressive mesenchymal glioblastoma subtype. The study found that LLMs get their cholesterol from myelin debris, which is the protective coating around nerve cells in the brain. LLMs then transfer this cholesterol to glioblastoma cells, which use it to fuel their high metabolic demands. The study's primary objective is to understand the immune-metabolic interplay during glioblastoma progression and identify targetable metabolic vulnerabilities in glioblastoma.

Abstract

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.

Overview

  • The study investigates the metabolic interplay between glioblastoma and its tumor microenvironment (TME) using single-cell and multi-omics analyses. The study identifies metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties, termed lipid-laden macrophages (LLMs). LLMs are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. The study also reveals that LLMs acquire an LLM phenotype by engulfing cholesterol-rich myelin debris and directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. The primary objective of the study is to understand the immune-metabolic interplay during glioblastoma progression and identify targetable metabolic vulnerabilities in glioblastoma.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties, termed lipid-laden macrophages (LLMs). LLMs are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. The study also reveals that LLMs acquire an LLM phenotype by engulfing cholesterol-rich myelin debris and directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. The key findings of the study are that LLMs are metabolically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. LLMs acquire an LLM phenotype by engulfing cholesterol-rich myelin debris and directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice. The study provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma. The study identifies metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties, termed lipid-laden macrophages (LLMs). LLMs are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. The study also reveals that LLMs acquire an LLM phenotype by engulfing cholesterol-rich myelin debris and directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. The study's limitations include the need for further validation of the findings in vivo and the need to investigate the role of LLMs in other types of tumors. Future research directions could include investigating the role of LLMs in other types of tumors, exploring the therapeutic potential of targeting LLMs, and investigating the role of LLMs in the development of drug resistance in glioblastoma.
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