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Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

ABSTRACT: Glioblastoma (GBM) is highly invasive primary brain tumor. Here, we retraced early steps of GBM invasion and interactions with tumor-associated myeloid cells (TAM) in a highly infiltrative murine GBM model in immunocompetent background. We reveal early mobilization of microglia in a wide onco-field ahead of GBM invasion, forming glial nets encircling tumor micro-infiltrates that are enmeshed with a dense network of extracellular matrix (ECM). Physical contacts with GBM cells initiate an astounding morphological, spatial, and functional transformation of microglia and monocyte-derived macrophages to form collectively organized migration streams with intertwined GBM cells, paralleled by major ECM restructuring along invasion tracks. Mechanistically, this requires upregulation of guidance receptor Plexin-B2 in TAM, which functions to resolve collisions with GBM cells by providing cell contact guidance for cell alignment and ECM restructuring. Together, our results on stage- and niche-specific mobilization of microglia/macrophages, on governing factors, and the molecular insights into pro-invasion signaling open new therapeutic opportunities to curb GBM invasion.

ORGANISM(S): Mus musculus

PROVIDER: GSE255289 | GEO | 2025/03/28

REPOSITORIES: GEO

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Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

Project description:Glioblastoma (GBM) is highly invasive primary brain tumor. Here, we retraced early steps of GBM invasion and interactions with tumor-associated myeloid cells (TAM) in a highly infiltrative murine GBM model in immunocompetent background. We reveal early mobilization of microglia in a wide onco-field ahead of GBM invasion, forming glial nets encircling tumor micro-infiltrates that are enmeshed with a dense network of extracellular matrix (ECM). Physical contacts with GBM cells initiate an astounding morphological, spatial, and functional transformation of microglia and monocyte-derived macrophages to form collectively organized migration streams with intertwined GBM cells, paralleled by major ECM restructuring along invasion tracks. Mechanistically, this requires upregulation of guidance receptor Plexin-B2 in TAM, which functions to resolve collisions with GBM cells by providing cell contact guidance for cell alignment and ECM restructuring. Together, our results on stage- and niche-specific mobilization of microglia/macrophages, on governing factors, and the molecular insights into pro-invasion signaling open new therapeutic opportunities to curb GBM invasion.

2025-03-28 | GSE275632 | GEO

An engineered glioblastoma model yields macrophage-secreted drivers of invasion

Project description:Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFβI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.

2023-12-21 | GSE251777 | GEO

Microglia and macrophages promote corralling, wound compaction and recovery in spinal cord injury via Plexin-B2

Project description:Tissue repair after spinal cord injury (SCI) requires mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment, and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core surrounded by an astrocytic border. Here, we elucidate a temporally distinct gene signature in injury-activated microglia/macrophages (IAM), which engages axon guidance pathways. Plexin-B2 is upregulated in IAM, which is required for motosensory recovery after SCI. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover, and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAM away from colliding cells, and facilitates matrix compaction. Our data thus establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAM with the injury microenvironment during wound healing.

2019-12-23 | GSE113566 | GEO

Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

Project description:Tumor-associated microglia and macrophages (TAM) are the most numerous non-neoplastic populations in the tumor microenvironment of glioblastoma (GBM), the most common malignant brain tumor in adulthood. The mTOR pathway, an important regulator of cell survival and proliferation, is known to be upregulated in GBM, but little is known about a potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Macrophages (TAM-BMDM) in in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-ĸB activity promotes an immunosuppressed phenotype in TAM-MG which hinders effector T cell proliferation and immune reactivity, thereby contributing to tumor immune evasion and promoting tumor growth in a mouse model. The translational value of these results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model whereby IPSC-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that tumor cells might not be the primary target of mTOR inhibition, and TAM-MG should be considered instead.

2020-07-21 | GSE147329 | GEO

Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

Project description:Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

| PRJNA1152278 | ENA

Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

Project description:Tumor-associated myeloid cells aid GBM infiltration by organizing invasion tracks via guidance receptor Plexin-B2

| PRJNA1074376 | ENA

Systematic identification of molecular pathways driving GBM invasion

Project description:Glioblastoma multiforme (GBM) is the most prevalent and deadliest adult brain tumor. To systematically characterize the pathways governing brain invasion, we developed a three-dimensional (3D) ex vivo organotypic invasion model with clinical relevance to GBM. We used this model to enrich for highly invasive GBM cell population. Using next-generation sequencing to transcriptomically profile highly invasive and poorly invasive GBM cell populations, we have identified a network of extracellular matrix (ECM) components, including multiple collagens and collagen-interacting proteins, which are upregulated by invading GBM cells and strongly correlate in expression with clinical glioma progression outcomes. We identify the interferon regulatory factor 3 (IRF3) as a direct transcriptional repressor of ECM factors in GBM and show that IRF3 acts as an endogenous suppressor of GBM invasion. Therapeutic activation of IRF3 by inhibiting casein kinase 2 (CK2) -- a negative regulator of IRF3 phosphorylation -- downregulated the expression of ECM factors and suppressed GBM invasion in ex vivo and in vivo models across a panel of patient-derived GBM cell lines representative of the main molecular GBM subtypes in the clinic. Our findings illustrate an integrated and systematic approach for the discovery of novel pathways regulating brain tumor invasion and provide a strong mechanistic insight into the notorious, yet poorly understood, invasion capacity of GBM tumors.

2017-10-01 | GSE87535 | GEO

Tumor-Associated Microglia Secrete Extracellular ATP to Support Glioblastoma Progression

Project description:Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis and high recurrence rates. The complex immune microenvironment of GBM is highly infiltrated by tumor-associated microglia and macrophages (TAMs). TAMs are known to be heterogeneous in their functional and metabolic states and can transmit either pro-tumoral or anti-tumoral signals to glioma cells. Here, we performed bulk RNA-seq and single-cell RNA-seq on GBM patient samples, which revealed increased ATP synthase expression and oxidative phosphorylation (OXPHOS) activity in TAMs located in the tumor core relative to the tumor periphery. Both in vitro and in vivo models displayed similar trends of augmented TAM mitochondrial activity, along with elevated mitochondrial fission, glucose uptake, mitochondrial membrane potential, and extracellular ATP (eATP) production by TAMs in the presence of GBM cells. Tumor-secreted factors, including GM-CSF, induced the increase in TAM eATP production. Elevated eATP in the GBM microenvironment promoted glioma growth and invasion by activating the P2X purinoceptor 7 (P2X7R) on glioma cells. Inhibition of the eATP-P2X7R axis attenuated tumor cell viability in vitro and reduced tumor size and prolonged survival in glioma-bearing mouse models. Overall, this study revealed elevated TAM-derived eATP in GBM and provided the basis for targeting the eATP-P2X7R signaling axis as a therapeutic strategy in GBM.

2024-08-30 | GSE275293 | GEO

Plexin-B2 reduces glioma cell cohesion and regulates glioma-vascular interactions

Project description:The diffuse invasion of glioblastoma (GBM) cells into healthy brain tissue is a main contributor for the high lethality of this most frequent form of malignant brain tumor. Plexins are cell surface receptors for semaphorins and control cell adhesion and cytoskeletal dynamics in development and in adult physiology. Gene expression of Plexin-B2 is upregulated in GBM and correlates with its lethality. We show here that Plexin-B2 activity can reduce the cohesiveness of GBM cells, which facilitates their invasive capacity. Targeted deletion of Plexin-B2 in GBM cells increased their cohesion to each other, revealing that a major function of Plexin-B2 activity is to downregulate cell-cell adhesion, possibly by downregulating other cell adhesion systems. In an in vivo intracranial transplant model, invasion of Plexin-B2 mutant GBM cells was impaired, with cells invading shorter distances. Interestingly, the loss of Plexin-B2 also changed the migration mode of cells, with the balance of cells in brain stroma vs. capillary space shifted: Plexin-B2 mutant cells were more likely to adhere to the vasculature. Our structure-function analyses revealed that the Ras-GAP domain of Plexin-B2 that is the main functional output responsible for the cohesion regulating function of Plexin-B2. Transcriptomic analyses of Plexin-B2 KO cells suggests that Plexin-B2 loss in different GBM cell lines has no direct transcriptional target genes, however, consistently, cell adhesion molecules were changed in expression, suggesting that cells compensate for loss of Plexin-B2. Thus, Plexin-B2 acts as a key regulator of the cohesiveness of GBM cells, thereby facilitating their invasiveness.

2021-01-13 | GSE126658 | GEO

Tumor progression is independent of tumor associated macrophages in two lineage-based mouse models of GBM [SortedTAM RNAseq]

Project description:We investigate whether TAM gene expression is similar between spontaneous and transplanted mouse models of GBM We sort Microglia and monocyte derived macrophages (MDM) from subventricular zone (type 1) and oligodendrocyte progenitor derived (type 2) spontaneous and transplanted mouse GBM tumors and perform bulk RNAseq

2023-03-06 | GSE225827 | GEO

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