Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Wang, Qianghu; Hu, Baoli; Hu, Xin; Kim, Hoon; Squatrito, Massimo; Scarpace, Lisa; deCarvalho, Ana C.; Lyu, Sali; Li, Pengping; Li, Yan; Barthel, Floris P.; Cho, Hee Jin; Lin, Yu; Satani, Nikunj; Martinez-Ledesma, Emmanuel; Zheng, Siyuan; Chang, Edward; Sauvé, Charles Etienne Gabriel; Olar, Adriana; Lan, Zheng D.; Finocchiaro, Gaetano; Phillips, Joanna J.; Berger, Mitchel S.; Gabrusiewicz, Konrad; Wang, Guocan; Eskilsson, Eskil; Hu, Jian; Mikkelsen, Tom; DePinho, Ronald A.; Müller, Florian; Heimberger, Amy B.; Sulman, Erik P.; Nam, Do Hyun; Verhaak, Roel G.W.

doi:10.1016/j.ccell.2017.12.012

Cited by 355 publications

(619 citation statements)

References 0 publications

Supporting

Mentioning

569

Contrasting

Order By: Relevance

“…In line with previous data (196 TCGA GBM samples classified into four subtypes ), LGR5 was significantly higher in proneural GSCs (Figure B), which was validated by RT‐qPCR for the majority of samples (Figure C). The relationship between the latest subtypes and LGR5 expression was investigated in 366 IDH wild‐type GBMs , which showed a significantly higher LGR5 expression in samples of the proneural subtype (Figure D).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

Xie

Sundström

Maturi

et al. 2019

The Journal of Pathology

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine‐rich repeat‐containing G‐protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient‐derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5high), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5‐responding cultures could be identified by their significantly higher self‐renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5high‐ELDAhigh cultures were also significantly more malignant and invasive compared to the LGR5high‐ELDAlow cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5‐responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient‐derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

Section: Resultsmentioning

confidence: 99%

“…One‐way ANOVA Dunnett's multiple comparisons test, **p < 0.01, ***p < 0.001. (D) LGR5 gene expression in 366 human IDH1/2 wild‐type GBM samples with assigned subtype . One‐way ANOVA Dunnett's multiple comparisons test, *p < 0.05.…”

Section: Resultsmentioning

confidence: 99%

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

Xie

Sundström

Maturi

et al. 2019

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…In GBMs, immunological signatures were found to differ between subtypes, with the mesenchymal‐like tumors harboring an enrichment of immune‐related genes . Moreover, compared with primary GBMs, recurrent GBMs demonstrated an altered composition of infiltrating immune cells, particularly a noted decrease in monocytes . Together, these findings illustrate the heterogeneity in brain tumors at multiple levels including inter‐patient, intratumoral, and within the TME.…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 84%

“…The existence of GBM subtypes helps explain the different responses to therapies, and some of the genetic signatures (eg, IDH1/2, MGMT, H3K27) have been used to guide diagnosis and treatment . The switch between subsets has also been shown to associate with tumor relapse . However, the complexity of brain tumor heterogeneity appears to go beyond the differential expression of certain genes and molecular subtypes.…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

167

161

View full text Add to dashboard Cite

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

show abstract

“…Their phenotype partly depends on the triggering event, which direct the balance between downstream inflammatory signaling pathways . While dominance of NFκB signaling has neurotoxic side‐effects , STAT3‐mediated reactivity is fundamental to create a trophic and less inflammatory milieu . Thus, the ability of glioma cells to mimic astrocyte reactivity likely plays an important role in shaping a tumor‐promoting microenvironment .…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity

Niklasson

Bergström

Jarvius

et al. 2019

The Journal of Pathology

View full text Add to dashboard Cite

Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma‐initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy‐resistant MES‐like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single‐cell level and strongly correlated with our previously defined therapy‐resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy‐resistant MES‐like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long‐term exposure to the proinflammatory cytokine interleukin 1 beta (IL1β). IL1β induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive‐astrocyte‐like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called ‘reactive GICs’. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor‐promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment‐resistant relapse‐driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

show abstract

Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment

Cited by 355 publications

References 0 publications

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

LGR5 promotes tumorigenicity and invasion of glioblastoma stem‐like cells and is a potential therapeutic target for a subset of glioblastoma patients

CAR T cells for brain tumors: Lessons learned and road ahead

Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity

Contact Info

Product

Resources

About