Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies

Abstract

SUMMARY Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone marrow-derived macrophages (BMDM) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDM. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDM are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDM are associated with tumor-mediated education, yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDM in primary and metastatic disease in mouse and human.

Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis

“…Metastasis to the anatomically closest site, the brain parenchyma, occurs in a densely cellular stroma dominated by endothelial cells, astrocytes, neurons, microglia, and the blood-brain barrier (Bos et al, 2009; Bowman et al, 2016; Chen et al, 2016; Sevenich et al, 2014; Valiente et al, 2014; Zhang et al, 2015). We compared the neuroanatomic localization of LeptoM derivatives with that of brain parenchymal metastatic derivatives (BrM cells) that were previously isolated from the same parental lines (Bos et al, 2009; Chen et al, 2016; Malladi et al, 2016; Nguyen et al, 2009) (Figure 1B).…”

Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade

“…In addition, transcriptional data of P2ry12 in a murine glioma model were obtained from the GEO database (GSE 86573) [3]. …”

The Microenvironmental Landscape of Brain Tumors

“…Ontogenetically distinct macrophage populations exist within the brain TME, including both tissue-resident microglia and bone marrow-derived macrophages (Bowman et al, 2016; Hambardzumyan et al, 2016)(Figure 1A). Microglia develop from embryonic yolk sac progenitor cells (Ginhoux et al, 2010; Gomez Perdiguero et al, 2015), and are not replenished postnatally through peripheral mononuclear hematopoiesis (Ajami et al, 2007).…”

“…Most studies that do not utilize lineage tracing have instead relied on differential CD45 expression levels to distinguish microglia (CD45 low ) from BMDMs (CD45 high ). However, while this approach is reasonably accurate for mouse models, it does not seem to hold true in human brain tumors (Bowman et al, 2016). In recent years, more accurate cell surface markers for flow cytometry that discriminate microglia and BMDMs have emerged.…”

“…Cx3cr1 and Siglec-H are also expressed by normal microglia, but not by macrophages derived from lung, peritoneum or spleen (Gautier et al, 2012). However, in brain tumors, subsequent studies have demonstrated that peripherally-derived macrophages can assimilate to the local TME upon entry into the brain, by upregulating ‘microglia-specific’ genes including Cx3cr1 (Bowman et al, 2016). In the context of brain malignancy, CD49D/ ITGA4 was recently identified as a marker for BMDMs but not microglia, thus enabling accurate discrimination and isolation of these distinct cell types in both patient and murine tumors (Bowman et al, 2016).…”