The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

Xie, Yuan; Bergström, Tobias; Jiang, Yiwen; Johansson, Patrik; Marinescu, Voichita D.; Lindberg, Nanna; Segerman, Anna; Wicher, Grzegorz; Niklasson, Mia; Baskaran, Sathishkumar; Sreedharan, Smitha; Everlien, Isabelle; Kastemar, Marianne; Hermansson, Annika; Elfineh, Lioudmila; Libard, Sylwia; Holland, Eric C.; Hesselager, Göran; Alafuzoff, Irina; Westermark, Bengt; Nelander, Sven; Forsberg-Nilsson, Karin; Uhrbom, Lene

doi:10.1016/j.ebiom.2015.08.026

Cited by 268 publications

(394 citation statements)

References 56 publications

Supporting

Mentioning

378

Contrasting

Order By: Relevance

“…To determine the diversity of heparan sulfate (HS) content and structure in human GBM, we profiled HS disaccharides isolated from patient-derived GBM lines maintained as tumorspheres using liquid chromatography mass spectrometry (LCMS). Tumor cells were cultured as tumorspheres, using neural stem cell conditions including non-adherent growth and minimal essential media, to promote retention of tumor generating cells (40,41). The four human lines were selected based on their diversity of molecular and transcriptional properties, including EGFR amplification and EGFRvIII expression in GBM6, PDGFRA amplification in GBM5, and CDKN2C/p18(INK4c) homozygous deletion in GBM43 (35,36,42).…”

Section: Resultsmentioning

confidence: 99%

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Tran

Wade

McKinney

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Tran

Wade

McKinney

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…In addition, these differences can be attributed to intratumoral subtype heterogeneity. 29,30 Tumors are distinct from PDCLs and usually cluster in 2 different groups. After exclusion of the differentially expressed genes, tumors clustered closely to their paired PDCLs.…”

Section: Neurooncologymentioning

confidence: 99%

Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors

Rosenberg

Verreault

Schmitt

et al. 2016

NEUONC

View full text Add to dashboard Cite

Background. Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTex project (GBM and Experimental Therapeutics) a GBM patient-derived cell line (GBM-PDCL) library. A multi-omic approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors. Methods. Single nucleotide polymorphism array, expression arrays, exome sequencing, and RNA sequencing were used to measure and compare the molecular landscapes of 20 samples representing 10 human GBM tumors and paired GBM-PDCLs. Results. Copy number variations were similar for a median of 85% of the genome and for 59% of the major focal events. Somatic point mutations were similar in a median of 41%. Mutations in GBM driver and "druggable" genes were maintained in 67% of events. Mutations that were not conserved in the PDCL were mainly low allelic fraction and/or non-driver mutations. Based on RNA expression profiling, PDCLs cluster closely to their parental tumor with overexpression of pathways associated with cancer progression in PDCL. Conclusions. Overall, PDCLs recapitulate pivotal molecular alterations of paired-parental tumors supporting their use as a preclinical model of GBM. However, some driver aberrations are lost or gained in the passage from tumor to PDCL. Our results support using PDCL as a relevant preclinical model of GBM. Further investigations of changes between PDCLs and their parental tumor may provide insights into GBM biology.

show abstract

“…In addition to these canonical adherent GBM cell lines, most analogues were more active than TMZ in the patient-derived U3054MG GBM cell line cultured under serum-free stem cell conditions. 31 …”

Section: Results and Discussionmentioning

confidence: 99%

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

et al. 2018

View full text Add to dashboard Cite

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

show abstract

The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes

Cited by 268 publications

References 56 publications

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion

Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

Contact Info

Product

Resources

About