Microglia and metastases to the central nervous system: victim, ravager, or something else?

Abstract

Central nervous system (CNS) metastases are a major cause of death in patients with cancer. Tumor cells must survive during their migration and dissemination in various sites and niches. The brain is considered an immunological sanctuary site, and thus the safest place for metastasis establishment. The risk of brain metastases is highest in patients with melanoma, lung, or breast cancers. In the CNS, metastatic cancer cells exploit the activity of different non-tumoral cell types in the brain microenvironment to create a new niche and to support their proliferation and survival. Among these cells, microglia (the brain resident macrophages) display an exceptional role in immune surveillance and tumor clearance. However, upon recruitment to the metastatic site, depending on the microenvironment context and disease conditions, microglia might be turned into tumor-supportive or -unsupportive cells. Recent single-cell ‘omic’ analyses have contributed to clarify microglia functional and spatial heterogeneity during tumor development and metastasis formation in the CNS. This review summarizes findings on microglia heterogeneity from classical studies to the new single-cell omics. We discuss i) how microglia interact with metastatic cancer cells in the unique brain tumor microenvironment; ii) the microglia classical M1-M2 binary concept and its limitations; and iii) single-cell omic findings that help to understand human and mouse microglia heterogeneity (core sensomes) and to describe the multi-context-dependent microglia functions in metastases to the CNS. We then propose ways to exploit microglia plasticity for brain metastasis treatment depending on the microenvironment profile.

Deciphering the impact of cancer cell’s secretome and its derived-peptide VGF on breast cancer brain metastasis

“…In addition to a restrictive vascular barrier, the brain is composed of unique resident cells, such as microglia, that play an important role in the immune response after injury. Accordingly, considering cancer progression, microglia cells were described as being responsible for identifying and attacking cancer cells that have invaded the brain (47,48). Nevertheless, some studies suggest that microglia can also promote the growth and spread of metastatic cells in the brain, contrasting with its tumor surveillance function (35)(36)(37)(38)(39)(40)(41).…”

Diffuse large B-cell lymphoma microenvironment displays a predominant macrophage infiltrate marked by a strong inflammatory signature

“…According to the classical M1/M2 concept, M0 macrophages can be reprogrammed into polarized M1 macrophages, a pro‐inflammatory phenotype with anti‐tumor activity, or to M2 immunosuppressive macrophages that contribute to tumor progression ( 17 ). However, the flexibly of M1/M2 polarity could completely change the outcome ( 21 ). Therefore, we hypothesized that the observed change in the cellular composition of the DLBCL microenvironment might imply a switch to a pro-inflammatory context.…”

Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer

“…The brain TME is enriched with various local brain cells such as microglia and astrocytes that have been shown to demonstrate this reciprocal interaction. Initially, microglia adopt an anti-tumor M1 phenotype but gradually transition to a pro-tumor M2 phenotype under the influence of tumor-derived cytokines, specifically STAT3 [18]. This M1-to-M2 shift has substantial implications, as a higher M2:M1 ratio is strongly associated with brain metastases.…”