Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma

Ravi, Vidhya; Will, Paulina; Kueckelhaus, Jan; Sun, Na; Joseph, Kevin; Salié, Henrike; Vollmer, Lea; Kuliesiute, Ugne; Ehr, Jasmin von; Benotmane, Jasim Kada; Neidert, Nicolas; Follo, Marie; Scherer, Florian; Goeldner, Jonathan M; Behringer, Sidney; Heiland, Dieter Henrik; Khiat, Mohammed; Zhang, Junyi; Hofmann, Ulrich G.; Fung, Christian; Ricklefs, Franz; Lamszus, Katrin; Boerries, Melanie; Ku, Manching; Beck, Jürgen; Sankowski, Roman; Schwabenland, Marius; Prinz, Marco; Schüller, Ulrich; Killmer, Saskia; Bengsch, Bertram; Walch, Axel; Delev, Daniel; Schnell, Oliver; Heiland, Dieter Henrik

doi:10.1016/j.ccell.2022.05.009

Cited by 228 publications

(314 citation statements)

References 82 publications

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“…Remodeling in response to hypoxic or low glucose environments occurs through various mechanisms including epigenetic modification ( 3 , 126 , 127 ), HIF-1α signaling ( 125 , 128 , 129 ), and altered expression of metabolic enzymes and transporters ( 49 , 130 ). In general, metabolic profiles in GBM cells are spatially distinct and attributed to TME interactions and restricted nutrient availability ( 122 , 125 , 131 , 132 ) with different GSC subsets having distinct metabolic preferences and dependencies ( 121 , 133 , 134 ).…”

Section: Contribution Of Gscs To the Immunosuppressive Microenvironme...mentioning

confidence: 99%

“…Al. define spatially distinct cellular phenotypes distinguished by transcriptional and metabolic programs through integration of spatial transcriptomics, MALDI-FTICR mass spectrometry, and mass cytometry proteomics ( 132 ). These five phenotypes were classified as radial glia, spatial OPC, neural development, reactive hypoxia, and reactive immune.…”

Section: Analytical Tools To Explore Gbm Heterogeneitymentioning

confidence: 99%

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Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

2022

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Despite its growing use in cancer treatment, immunotherapy has been virtually ineffective in clinical trials for gliomas. The inherently cold tumor immune microenvironment (TIME) in gliomas, characterized by a high ratio of pro-tumor to anti-tumor immune cell infiltrates, acts as a seemingly insurmountable barrier to immunotherapy. Glioma stem cells (GSCs) within these tumors are key contributors to this cold TIME, often functioning indirectly through activation and recruitment of pro-tumor immune cell types. Furthermore, drivers of GSC plasticity and heterogeneity (e.g., reprogramming transcription factors, epigenetic modifications) are associated with induction of immunosuppressive cell states. Recent studies have identified GSC-intrinsic mechanisms, including functional mimicry of immune suppressive cell types, as key determinants of anti-tumor immune escape. In this review, we cover recent advancements in our understanding of GSC-intrinsic mechanisms that modulate GSC-TIME interactions and discuss cutting-edge techniques and bioinformatics platforms available to study immune modulation at high cellular resolution with exploration of both malignant (i.e., GSC) and non-malignant (i.e., immune) cell fractions. Finally, we provide insight into the therapeutic opportunities for targeting immunomodulatory GSC-intrinsic mechanisms to potentiate immunotherapy response in gliomas.

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Section: Contribution Of Gscs To the Immunosuppressive Microenvironme...mentioning

confidence: 99%

Section: Analytical Tools To Explore Gbm Heterogeneitymentioning

confidence: 99%

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

2022

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“…To that end, MES-like hypoxia-dependent and hypoxia- in dependent cells, as well as AC-like glioblastoma cells were used and their response to chemical hypoxia alone or in combination with extracellular acidosis was investigated. Considering that the cell states described by Neftel et al [ 10 ] have a high degree of plasticity and are likely to shift according to the microenvironment into NPC-like or OPC-like states, recent work has shown that, in cell culture conditions, predominantly the MES- and AC-like states are maintained [ 11 ]. Although it is expected that hypoxia treatment of the cells results in a transcriptional shift towards the hypoxia-dependent state, the respective adaptation is found to be heterogeneous.…”

Section: Discussionmentioning

confidence: 99%

“…Three cell lines were established and classified using bulk RNA-seq according to the transcriptional classification [ 10 , 11 , 42 ]. The GBM cells are distinguished based on their gene expression profiles.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, the MES-like subtype has been further categorized into hypoxia-dependent and a hypoxia- in dependent subgroups based on the strong association with hypoxia-response-, stress-, and glycolytic genes expression [ 10 ]. The most recent classification of the spatial architecture of glioblastoma confirmed that the hypoxia-associated gene expression subgroup occupied segregated niches within the tumour highly associated with genomic instability and tumour resistance [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Cell-Type Dependent Regulation of the Electrogenic Na+/HCO3− Cotransporter 1 (NBCe1) by Hypoxia and Acidosis in Glioblastoma

Giannaki

Ruf

Pfeifer

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is the most common and malignant brain tumour. It is characterised by transcriptionally distinct cell populations. In tumour cells, physiological pH gradients between the intracellular and extracellular compartments are reversed, compared to non-cancer cells. Intracellular pH in tumour cells is alkaline, whereas extracellular pH is acidic. Consequently, the function and/or expression of pH regulating transporters might be altered. Here, we investigated protein expression and regulation of the electrogenic sodium/bicarbonate cotransporter 1 (NBCe1) in mesenchymal (MES)-like hypoxia-dependent and -independent cells, as well as in astrocyte-like glioblastoma cells following chemical hypoxia, acidosis and elucidated putative underlying molecular pathways. Immunoblotting, immunocytochemistry, and intracellular pH recording with the H+-sensitive dye 2′,7′-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein were applied. The results show NBCe1 protein abundance and active NBCe1 transport. Hypoxia upregulated NBCe1 protein and activity in MES-like hypoxia-dependent GBM cells. This effect was positively correlated with HIF-1a protein levels, was mediated by TGF-b signalling, and was prevented by extracellular acidosis. In MES-like hypoxia-independent GBM cells, acidosis (but not hypoxia) regulated NBCe1 activity in an HIF-1a-independent manner. These results demonstrate a cell-specific adaptation of NBCe1 expression and activity to the microenvironment challenge of hypoxia and acidosis that depends on their transcriptional signature in GBM.

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Microglia and macrophages in glioblastoma: landscapes and treatment directions

Solomou,

Young,

Bulstrode

2024

Molecular Oncology

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Glioblastoma is the most common primary malignant tumour of the central nervous system and remains uniformly and rapidly fatal. The tumour‐associated macrophage (TAM) compartment comprises brain‐resident microglia and bone marrow‐derived macrophages (BMDMs) recruited from the periphery. Immune‐suppressive and tumour‐supportive TAM cell states predominate in glioblastoma, and immunotherapies, which have achieved striking success in other solid tumours have consistently failed to improve survival in this ‘immune‐cold’ niche context. Hypoxic and necrotic regions in the tumour core are found to enrich, especially in anti‐inflammatory and immune‐suppressive TAM cell states. Microglia predominate at the invasive tumour margin and express pro‐inflammatory and interferon TAM cell signatures. Depletion of TAMs, or repolarisation towards a pro‐inflammatory state, are appealing therapeutic strategies and will depend on effective understanding and classification of TAM cell ontogeny and state based on new single‐cell and spatial multi‐omic in situ profiling. Here, we explore the application of these datasets to expand and refine TAM characterisation, to inform improved modelling approaches, and ultimately underpin the effective manipulation of function.

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Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma

Cited by 228 publications

References 82 publications

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

Exploring glioblastoma stem cell heterogeneity: Immune microenvironment modulation and therapeutic opportunities

Cell-Type Dependent Regulation of the Electrogenic Na+/HCO3− Cotransporter 1 (NBCe1) by Hypoxia and Acidosis in Glioblastoma

Microglia and macrophages in glioblastoma: landscapes and treatment directions

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