Cellular Architecture of Human Brain Metastases

González, Hugo; Mei, Wenbin; Robles, Isabella; Hagerling, Catharina; Allen, Breanna M.; Nanjaraj, Ankitha; Verbeek, Tamara; Kalavacherla, Sandhya; Gogh, Merel van; Georgiou, Stephen; Daras, Mariza; Philips, Joanna J.; Spitzer, Matthew H.; Roose, Jeroen P.; Werb, Zena

doi:10.2139/ssrn.3883639

Cited by 8 publications

(12 citation statements)

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“…Gene Ontology analysis confirmed distinct functions across the Mo/Mg‐TAM subsets (supplementary material, Figure S4D). Thus, as recently reported in TAMs from human brain metastases [24], the functional states of ontogenically different TAMs in brain tumours could be more complex than the prototypical M1 (pro‐inflammatory) or M2 (immunosuppressive) paradigm.…”

Section: Resultsmentioning

confidence: 76%

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

Yin

Ping

et al. 2022

The Journal of Pathology

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Tumour‐associated macrophages (TAMs) abundantly infiltrate high‐grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)‐differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte‐derived TAM (Mo‐TAM) and microglia‐derived TAM (Mg‐TAM) clusters across glioblastoma‐IDH‐wild type and astrocytoma‐IDH‐mutant‐grade 4 (Astro‐IDH‐mut‐G4). Single‐cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro‐IDH‐mut‐G4. Cell clustering, single‐cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM‐cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro‐IDH‐mut‐G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg‐TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg‐TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset‐specific markers identified spatial enrichment of distinct TAM clusters at peri‐vascular/necrotic areas in tumour parenchyma or at the tumour–brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo‐TAM‐inflammatory clusters, whereas Astro‐IDH‐mut‐G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH‐differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 76%

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

Yin

Ping

et al. 2022

The Journal of Pathology

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“…One other limitation in this study is the limited number of cases per group that restricts our capabilities to demonstrate specific characteristics for cancer types and subtypes. This type of analysis does not lend itself to high-volume throughput of specimens (65). In fact, patients with high-grade cancer are exposed to multiple regimens of therapies, which makes it a challenge to have comparable patient groups with higher number of patients between primary and metastatic brain cancers.…”

Section: Jcimentioning

confidence: 99%

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression

Najem¹,

Ott²,

Kassab³

et al. 2022

JCI Insight

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“…But cancer and non‐cancer constituents of the TME surely communicate among one another contemporaneously and bidirectionally, just as microglia, astrocytes, and immune cells cooperate to address brain injury. High‐resolution omics technologies are starting to reveal a dense web of interactions between cell types in MBM at unprecedented spatial and molecular detail (Lawson et al 2018, Smalley et al 2021, Gonzalez et al 2022).…”

Section: Molecular Determinants Of Melanoma Brain Metastasismentioning

confidence: 99%

“…But cancer and non-cancer constituents of the TME surely communicate among one another contemporaneously and bidirectionally, just as microglia, astrocytes, and immune cells cooperate to address brain injury. High-resolution omics technologies are starting to reveal a dense web of interactions between cell types in MBM at unprecedented spatial and molecular detail(Lawson et al 2018, Smalley et al 2021, Gonzalez et al 2022.The relative geographic orientation of the cells of the TME has biological import in other malignancies and may therefore represent a dimension of information worth exploring in MBM. For example, glioblastoma cells exhibit distinct phenotypes across the tumor's "heterogeneous landscape of cell populations"(Comba et al 2021); proximity to synapses allows breast cancer brain metastatic cells to engage with neurons where astrocytes usually do(Zeng et al 2019);…”

mentioning

confidence: 99%

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

Karz

Dimitrova

Kleffman

et al. 2022

Pigment Cell Melanoma Res

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Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients.The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

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Cellular Architecture of Human Brain Metastases

Cited by 8 publications

References 0 publications

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

A map of the spatial distribution and tumour‐associated macrophage states in glioblastoma and grade 4 IDH‐mutant astrocytoma

Central nervous system immune interactome is a function of cancer lineage, tumor microenvironment, and STAT3 expression

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

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