Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment

Wang, Qianghu; Hu, Xin; Hu, Baoli; Müller, Florian; Kim, Hoon; Squatrito, Massimo; Mikkelsen, Tom; Scarpace, Lisa; Barthel, Floris P.; Lin, Yu-Hsi; Satani, Nikunj; Martínez-Ledesma, Emmanuel; Chang, Edward F.; Olar, Adriana; Wang, Guocan; deCarvalho, Ana; Eskilsson, Eskil; Zheng, Siyuan; Heimberger, Amy B.; Sulman, Erik P.; Nam, Do‐Hyun; Verhaak, Roel G.W.

doi:10.1101/052076

Cited by 31 publications

(39 citation statements)

References 58 publications

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“…This phenomenon has been observed in 66 single cells in a HGSC tumor [87] and a subset of glioblastoma tumors by single cell profiling [88]. However, it has been recently shown that glioblastoma tumors are inherently heterogeneous by chance [89], and more single cell data is required to fully explore this phenomenon. Single cell RNAseq can reveal the types of cells in a complex mixture [90].…”

Section: Characteristics Of Hgsc Molecular Subtypesmentioning

confidence: 94%

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

et al. 2017

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Purpose of review Only recently has it become clear that epithelial ovarian cancer (EOC) is comprised of such distinct histotypes--with different cells of origin, morphology, molecular features, epidemiologic factors, clinical features, and survival patterns—that they can be thought of as different diseases sharing an anatomical location. Herein, we review opportunities and challenges in studying EOC heterogeneity, Recent findings The 2014 World Health Organization diagnostic guidelines incorporate accumulated evidence that high- and low-grade serous tumors have different underlying pathogenesis, and that, on the basis of shared molecular features, most high grade tumors, including some previously classified as endometrioid, are now considered to be high-grade serous. At the same time, several studies have reported that high-grade serous EOC, which is the most common histotype, is itself made up of reproducible subtypes discernable by gene expression patterns. Summary These major advances in understanding set the stage for a new era of research on EOC risk and clinical outcomes with the potential to reduce morbidity and mortality. We highlight the need for multidisciplinary studies with pathology review using the current guidelines, further molecular characterization of the histotypes and subtypes, inclusion of women of diverse racial/ethnic and socioeconomic backgrounds, and updated epidemiologic and clinical data relevant to current generations of women at risk of EOC.

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Section: Characteristics Of Hgsc Molecular Subtypesmentioning

confidence: 94%

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

et al. 2017

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“…Despite this heterogeneity transcriptional profiling has identified tumor subtypes (1,2) with enrichment of specific cell signaling (3), proteomic (4,5) and immune cell characteristics (6,7). The design of improved therapeutics for GBM requires an understanding of intertumoral heterogeneity and its potential impact on therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Tran

Wade

McKinney

et al. 2017

Molecular Cancer Research

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Glioblastoma (GBM) is the most common primary malignant brain tumor of adults and confers a poor prognosis due, in part, to diffuse invasion of tumor cells. Heparan sulfate (HS) glycosaminoglycans, present on the cell surface and in the extracellular matrix, regulate cell signaling pathways and cell-microenvironment interactions. In GBM, the expression of HS glycosaminoglycans and the enzymes that regulate their function are altered but the actual HS content and structure are unknown. However, inhibition of HS glycosaminoglycan function is emerging as a promising therapeutic strategy for some cancers. In this study, we use liquid chromatography-mass spectrometry (LC/MS) analysis to demonstrate differences in HS disaccharide content and structure across four patient-derived tumorsphere lines (GBM1, 5, 6, 43) and between two murine tumorsphere lines derived from murine GBM with enrichment of mesenchymal and proneural gene expression (mMES and mPN, respectively) markers. In GBM, the heterogeneous HS content and structure across patient-derived tumorsphere lines suggested diverse functions in the GBM tumor microenvironment (TME). In GBM5 and mPN, elevated expression of sulfatase 2 (SULF2), an extracellular enzyme that alters ligand binding to HS, was associated with low trisulfated HS disaccharides, a substrate of SULF2. In contrast, other primary tumorsphere lines had elevated expression of the HS-modifying enzyme heparanase (HPSE). Using gene editing strategies to inhibit HPSE a role for HPSE in promoting tumor cell adhesion and invasion was identified. These studies characterize the heterogeneity in HS glycosaminoglycan content and structure across GBM and reveal their role in tumor cell invasion.

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“…Molecular analyses comparing SFCs and ESCs sustained the notion that ESCs could be more dependent on exogenous stimuli. They formed a distinct subgroup in relation to the SFCs and were all assigned to the mesenchymal subtype, which has been demonstrated to have the highest influence of microenvironmental induced gene expression (Wang et al, ). ESCs continued to upregulate genes and pathways induced by exogenous stimuli also after being switched to SF culture conditions, which implied that they were derived from GBMs that were intrinsically different compared to those generating SFCs.…”

Section: Discussionmentioning

confidence: 99%

“…The raw data was RMA‐normalized using R‐library oligo (Carvalho & Irizarry, ). The SFC, ESC, and ESC_to_SFC samples were given subtype affiliations using ssGSEA analogous to the method as described previously (Wang et al, ). Hierarchical clustering was performed using R‐function hclust with complete linkage as an agglomeration method.…”

Section: Methodsmentioning

confidence: 99%

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

Maturi

Tan

Xie

et al. 2019

Glia

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Glioblastoma (GBM) is the most frequent and deadly primary malignant brain tumor. Hallmarks are extensive intra‐tumor and inter‐tumor heterogeneity and highly invasive growth, which provide great challenges for treatment. Efficient therapy is lacking and the majority of patients survive less than 1 year from diagnosis. GBM progression and recurrence is caused by treatment‐resistant glioblastoma stem cells (GSCs). GSC cultures are considered important models in target identification and drug screening studies. The current state‐of‐the‐art method, to isolate and maintain GSC cultures that faithfully mimic the primary tumor, is to use serum‐free (SF) media conditions developed for neural stem cells (NSCs). Here we have investigated the outcome of explanting 218 consecutively collected GBM patient samples under both SF and standard, serum‐containing media conditions. The frequency of maintainable SF cultures (SFCs) was most successful, but for a subgroup of GBM specimens, a viable culture could only be established in serum‐containing media, called exclusive serum culture (ESC). ESCs expressed nestin and SOX2, and displayed all functional characteristics of a GSC, that is, extended proliferation, sustained self‐renewal and orthotopic tumor initiation. Once adapted to the in vitro milieu they were also sustainable in SF media. Molecular analyses showed that ESCs formed a discrete group that was most related to the mesenchymal GBM subtype. This distinct subgroup of GBM that would have evaded modeling in SF conditions only provide unique cell models of GBM inter‐tumor heterogeneity.

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Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment

Cited by 31 publications

References 58 publications

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

Challenges and Opportunities in Studying the Epidemiology of Ovarian Cancer Subtypes

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

A molecularly distinct subset of glioblastoma requires serum‐containing media to establish sustainable bona fide glioblastoma stem cell cultures

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