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 340 publications

(349 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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“…Interestingly, hypoxia activated the ANXA2–STAT3–OSMR signalling axis [ 145 ]. Moreover, it has been recently published that mesenchymal-like transitions in glioblastoma cells are driven by macrophage-derived OSM [ 146 ].…”

Section: Role Of Il-6 and Osm In Epithelial–mesenchymal Plasticitymentioning

confidence: 99%

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

Abaurrea

Araujo

Caffarel

2021

IJMS

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Epithelial–mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.

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

Cited by 340 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

The Role of the IL-6 Cytokine Family in Epithelial–Mesenchymal Plasticity in Cancer Progression

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