Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Greenwald, Alissa C.; Darnell, Noam Galili; Hoefflin, Rouven; Simkin, Dor; Mount, Christopher W.; Gonzalez Castro, L. Nicolas; Harnik, Yotam; Dumont, Sydney; Hirsch, Dana; Nomura, Masashi; Talpir, Tom; Kedmi, Merav; Goliand, Inna; Medici, Gioele; Laffy, Julie; Li, Baoguo; Mangena, Vamsi; Keren-Shaul, Hadas; Weller, Michael; Addadi, Yoseph; Neidert, Marian C.; Suvà, Mario L.; Tirosh, Itay

doi:10.1016/j.cell.2024.03.029

Cited by 21 publications

(11 citation statements)

References 71 publications

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“…Recently, two studies have gleaned into the spatial heterogeneity of GBM and identified hypoxia as one of the major factors influencing transcriptional cell states within the tumor tissue (3,4). Spatial gradient of hypoxia results in a concentric organization of cellular states with mesenchymal features surrounded by hypoxia-responsive cell states and vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…Amplifications of EGFR, CDK4 and PDGFRA are associated with astrocyte-like (AC-like), neural progenitor cell-like (NPC-like), and oligodendrocytic precursor cell-like (OPC-like) states, respectively. Recent advances in spatial profiling facilitated the investigation of the architecture of GBM tissues and allowed for the identification of several patterns of spatial organization in these tumors (3,4). However, the link between genetically defined subpopulations and their microenvironment and changes in these relationships that may drive recurrence remain to be further investigated.…”

Section: Introductionmentioning

confidence: 99%

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Spatial analysis of recurrent glioblastoma reveals perivascular niche organization

Onubogu,

Gatenbee,

Prabhakaran

et al. 2024

JCI Insight

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Tumor evolution is driven by genetic variation; however, it is the tumor microenvironment (TME) that provides the selective pressure contributing to evolution in cancer. Despite high histopathological heterogeneity within glioblastoma (GBM), the most aggressive brain tumor, the interactions between the genetically distinct GBM cells and the surrounding TME are not fully understood. To address this, we analyzed matched primary and recurrent GBM archival tumor tissues with imaging-based techniques aimed to simultaneously evaluate tumor tissues for presence of hypoxic, angiogenic, and inflammatory niches, extracellular matrix organization, TERT promoter mutational status, and several oncogenic amplifications on the same slide and location. We found that the relationships between genetic and TME diversity are different in primary and matched recurrent tumors. Interestingly, the texture of the extracellular matrix (ECM), identified by label-free reflectance imaging, was predictive of single-cell genetic traits present in the tissue. Moreover, reflectance of ECM revealed structured organization of the perivascular niche in recurrent GBM, enriched in immunosuppressive macrophages.Single-cell spatial transcriptomics further confirmed the presence of the niche-specific macrophage populations and identified interactions between endothelial cells, perivascular fibroblasts, and immunosuppressive macrophages. Our results underscore the importance of GBM tissue organization in tumor evolution and highlight novel genetic and spatial dependencies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization

Onubogu,

Gatenbee,

Prabhakaran

et al. 2024

JCI Insight

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“…Most recently, the emergence of spatial transcriptomics has permitted a deeper investigation of cellular interactions within the TME and optimal delineation of cellular niches within the tumor [ 69 , 70 , 71 ]. In a very recent study, Greenwald et al defined GBM cellular states and uncovered their organization through approaches combining spatial transcriptomics, spatial proteomics, and computational analysis [ 72 ]. Their findings indicated that GBM tumors contain both disorganized and structured regions, whereby the organized regions were associated with an abundance of MES-hypoxic cancer cells that extended beyond what could be observed in histopathology.…”

Section: Heterogeneity In Gbmmentioning

confidence: 99%

The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma

Wu,

Berglund,

Macaulay

et al. 2024

Cells

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Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype. Furthermore, it is universally recognized that a small subset of GBM cells known as GBM stem cells (GSCs) serve as reservoirs for tumor recurrence and progression. The clonal evolution of GSC molecular subtypes in response to therapy drives intra-tumoral heterogeneity and remains a critical determinant of GBM outcomes. In particular, the intra-tumoral MES reprogramming of GSCs using current GBM therapies has emerged as a leading hypothesis for therapeutic refractoriness. Preventing the intra-tumoral divergent evolution of GBM toward the MES subtype via new treatments would dramatically improve long-term survival for GBM patients and have a significant impact on GBM outcomes. In this review, we examine the challenges of the role of MES reprogramming in the malignant clonal evolution of glioblastoma and provide future perspectives for addressing the unmet therapeutic need to overcome resistance in GBM.

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“…Microglia display remarkable plasticity, constantly surveying their local environment and responding to brain insults, including tumors, by engaging specific sets of transcription factors to activate new gene expression programs that yield distinct phenotypic states 9,10 . TAM-MG phenotypes in GBM are diverse and complex due to the heterogeneous nature of the tumors, a consequence of dynamic shifts in proportions of infiltrating immune cells, multiple tumor cell lineages, and niches of necrosis, uncontrolled proliferation, and hypoxia 11 . Often, TAM-MGs display tumor-supportive and tumor-killing phenotypes in the same tumor, based on the local signals TAM-MGs encounter, leading to immunologically hot and cold regions of the tumor that are difficult to treat [12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

Tharp,

Han,

Balak

et al. 2024

Preprint

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SummaryBiological sex is an important risk factor in cancer, but the underlying cell types and mechanisms remain obscure. Since tumor development is regulated by the immune system, we hypothesize that sex-biased immune interactions underpin sex differences in cancer. The male-biased glioblastoma multiforme (GBM) is an aggressive and treatment-refractory tumor in urgent need of more innovative approaches, such as considering sex differences, to improve outcomes. GBM arises in the specialized brain immune environment dominated by microglia, so we explored sex differences in this immune cell type. We isolated adult human TAM-MGs (tumor-associated macrophages enriched for microglia) and control microglia and found sex-biased inflammatory signatures in GBM and lower-grade tumors associated with pro-tumorigenic activity in males and anti-tumorigenic activity in females. We demonstrated that genes expressed or modulated by the inactive X chromosome facilitate this bias. Together, our results implicate TAM-MGs, specifically their sex chromosomes, as drivers of male bias in GBM.

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Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Cited by 21 publications

References 71 publications

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization

Spatial analysis of recurrent glioblastoma reveals perivascular niche organization

The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma

The inactive X chromosome drives sex differences in microglial inflammatory activity in human glioblastoma

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