Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Hara, Toshiro; Chanoch-Myers, Rony; Mathewson, Nathan D.; Myskiw, Chad; Atta, Lyla; Bussema, Lillian; Eichhorn, Stephen W.; Greenwald, Alissa C.; Kinker, Gabriela Sarti; Rodman, Christopher; Castro, L Nicolas Gonzalez; Wakimoto, Hiroaki; Rozenblatt-Rosen, Orit; Zhuang, Xiaowei; Fan, Jean; Hunter, Tony; Verma, Inder M.; Wucherpfennig, Kai W.; Regev, Aviv; Suvà, Mario L.; Tirosh, Itay

doi:10.1016/j.ccell.2021.05.002

Cited by 269 publications

(231 citation statements)

References 60 publications

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“…The most broadly accepted transcriptional classification of GBM was originally based on gene expression profiles of bulk tumors ( Verhaak et al, 2010 ), which did not discriminate the contribution of tumor cells and TME to the transcriptional signatures. It is now becoming evident that both cell-intrinsic and -extrinsic cues can contribute to the specification of the MES subtype ( Bhat et al, 2013 ; Hara et al, 2021 ; Neftel et al, 2019 ; Schmitt et al, 2021 ; Wang et al, 2017 ). Bhat and colleagues had shown that while some of the MES GBMs maintained the mesenchymal characteristics when expanded in vitro as BTSCs, some others lost the MGS after few passages while exhibiting a higher non-MGSs ( Bhat et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1

Marques

Unterkircher

Kroon

et al. 2021

eLife

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The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor FOSL1 as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of FOSL1 expression. Depletion of FOSL1 in NF1-mutant human BTSCs and Kras-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that FOSL1 controls GBM plasticity and aggressiveness in response to NF1 alterations.

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Section: Discussionmentioning

confidence: 99%

NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1

Marques

Unterkircher

Kroon

et al. 2021

eLife

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“…The proneural subtype GBMs, which show the best prognosis among the three molecular subtypes, had significantly lower signature of CD4+ T-cells and the classical GBM showed significantly stronger dendritic cell signature [66]. Hara et al (2021) performed an extensive investigation of the cross-talk between the immune microenvironment and the mesenchymal GBM subtype [71]. Using a mouse glioma model induced via transduction with the lentivirus harboring GFP, Hras G12V and sh-p53, the authors confirmed a presence of the tumor cell states consistent with the ones observed in human glioblastomas [12].…”

Section: Immune Microenvironment In the Molecular Subtypes Of Gbmmentioning

confidence: 98%

“…Hara et al (2021) performed an extensive investigation of the cross-talk between the immune microenvironment and the mesenchymal GBM subtype [ 71 ]. Using a mouse glioma model induced via transduction with the lentivirus harboring GFP, Hras G12V and sh-p53, the authors confirmed a presence of the tumor cell states consistent with the ones observed in human glioblastomas [ 12 ].…”

Section: Immune Microenvironment Of Malignant Gliomas—insights From Single-cell Omicsmentioning

confidence: 99%

Single-Cell Omics in Dissecting Immune Microenvironment of Malignant Gliomas—Challenges and Perspectives

Kamińska

Ochocka

Segit

2021

Cells

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Single-cell technologies allow precise identification of tumor composition at the single‑cell level, providing high-resolution insights into the intratumoral heterogeneity and transcriptional activity of cells in the tumor microenvironment (TME) that previous approaches failed to capture. Malignant gliomas, the most common primary brain tumors in adults, are genetically heterogeneous and their TME consists of various stromal and immune cells playing an important role in tumor progression and responses to therapies. Previous gene expression or immunocytochemical studies of immune cells infiltrating TME of malignant gliomas failed to dissect their functional phenotypes. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) are powerful techniques allowing quantification of whole transcriptomes or >30 protein targets in individual cells. Both methods provide unprecedented resolution of TME. We summarize the findings from these studies and the current state of knowledge of a functional diversity of immune infiltrates in malignant gliomas with different genetic alterations. A precise definition of functional phenotypes of myeloid and lymphoid cells might be essential for designing effective immunotherapies. Single-cell omics studies have identified crucial cell subpopulations and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy. We anticipate that the widespread usage of single-cell omics would allow rational design of oncoimmunotherapeutics.

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“…Stat3 is a critical mediator of immune related responses in gliomas [ 59 , 60 ]. Interactions between microglia and glioma tumor cells can promote a mesenchymal cell state in glioma tumor cells, which is dependent on Stat3 activation [ 61 ]. Additionally, increased cytokine expression caused by interactions between microglia and glioma cells can activate endothelial Jak / Stat3 signaling, resulting in increased vascular permeability in vitro [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

Wei

Meel

Breur

et al. 2021

acta neuropathol commun

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The blood–brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.

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Interactions between cancer cells and immune cells drive transitions to mesenchymal-like states in glioblastoma

Cited by 269 publications

References 60 publications

NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1

NF1 regulates mesenchymal glioblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1

Single-Cell Omics in Dissecting Immune Microenvironment of Malignant Gliomas—Challenges and Perspectives

Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas

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