Culture methods of diffuse intrinsic pontine glioma cells determine response to targeted therapies

Meel, Michaël H.; Sewing, A.; Waranecki, Piotr; Metselaar, Dennis S.; Wedekind, Laurine E.; Koster, Jan; Vuurden, Dannis G. van; Kaspers, Gertjan J. L.; Hulleman, Esther

doi:10.1016/j.yexcr.2017.09.032

Cited by 26 publications

(29 citation statements)

References 42 publications

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“…Some other publications supported an equivalence of 2D and 3D cultures for modeling drug response [17,32]. Others articles described the genomic differences of paired adult HGG NSs and MNLs, as observed in our experiments, and how the collaboration between subclonal cell populations determines drug response [18,19,33,34]. We demonstrated here that 3D/NS were sensitive to a high dose of TMZ, while the paired-MNL cells were totally resistant to this drug.…”

Section: Discussionsupporting

confidence: 82%

“…Therefore, we believe that the isolation of those cell types (2D and 3D cultures) from the same tumor patient might accurately recreate the multilineage organization of the pHGGs to study the drug response in vitro. This will take into account the differentiation hierarchies of tumor cells involved in tumor development and in drug resistance [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

Blandin

Durand

Litzler

et al. 2019

Cancers

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Background: Pediatric high-grade gliomas (pHGGs) are facing a very dismal prognosis and representative pre-clinical models are needed for new treatment strategies. Here, we examined the relevance of collecting functional, genomic, and metabolomics data to validate patient-derived models in a hypoxic microenvironment. Methods: From our biobank of pediatric brain tumor-derived models, we selected 11 pHGGs driven by the histone H3.3K28M mutation. We compared the features of four patient tumors to their paired cell lines and mouse xenografts using NGS (next generation sequencing), aCGH (array comparative genomic hybridization), RNA sequencing, WES (whole exome sequencing), immunocytochemistry, and HRMAS (high resolution magic angle spinning) spectroscopy. We developed a multicellular in vitro model of cell migration to mimic the brain hypoxic microenvironment. The live cell technology Incucyte© was used to assess drug responsiveness in variable oxygen conditions. Results: The concurrent 2D and 3D cultures generated from the same tumor sample exhibited divergent but complementary features, recreating the patient intra-tumor complexity. Genomic and metabolomic data described the metabolic changes during pHGG progression and supported hypoxia as an important key to preserve the tumor metabolism in vitro and cell dissemination present in patients. The neurosphere features preserved tumor development and sensitivity to treatment. Conclusion: We proposed a novel multistep work for the development and validation of patient-derived models, considering the immature and differentiated content and the tumor microenvironment of pHGGs.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

Blandin

Durand

Litzler

et al. 2019

Cancers

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“…In glioblastoma, both AXL and MERTK have been identified as potential therapeutic targets and causes of treatment resistance. Inhibition of AXL and/or MERTK leads to diminished proliferation, migration and invasion of glioma cells, as well as sensitization of glioma cells to chemotherapy [ 174 – 180 ] Although specific studies addressing the biological role of the TAM RTKs in pediatric HGG and DIPG are not available, overexpression of both AXL and MERTK has been described, and AXL has been shown to be activated in cultured DIPG cells [ 180 , 181 ].…”

Section: External Initiation Of the Epithelial-to-mesenchymal Transitmentioning

confidence: 99%

Signaling pathways and mesenchymal transition in pediatric high-grade glioma

Meel

Schaper

Kaspers

et al. 2017

Cell. Mol. Life Sci.

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Pediatric high-grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPG), are the most lethal types of cancer in children. In recent years, it has become evident that these tumors are driven by epigenetic events, mainly mutations involving genes encoding Histone 3, setting them apart from their adult counterparts. These tumors are exceptionally resistant to chemotherapy and respond only temporarily to radiotherapy. Moreover, their delicate location and diffuse growth pattern make complete surgical resection impossible. In many other forms of cancer, chemo- and radioresistance, in combination with a diffuse, invasive phenotype, are associated with a transcriptional program termed the epithelial-to-mesenchymal transition (EMT). Activation of this program allows cancer cells to survive individually, invade surrounding tissues and metastasize. It also enables them to survive exposure to cytotoxic therapy, including chemotherapeutic drugs and radiation. We here suggest that EMT plays an important, yet poorly understood role in the biology and therapy resistance of pHGG and DIPG. This review summarizes the current knowledge on the major signal transduction pathways and transcription factors involved in the epithelial-to-mesenchymal transition in cancer in general and in pediatric HGG and DIPG in particular. Despite the fact that the mesenchymal transition has not yet been specifically studied in pHGG and DIPG, activation of pathways and high levels of transcription factors involved in EMT have been described. We conclude that the mesenchymal transition is likely to be an important element of the biology of pHGG and DIPG and warrants further investigation for the development of novel therapeutics.

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“…Cell lines: Patient-derived K27M SU-DIPG-IV (IV, H3.1K27M), SU-DIPG-XXXVI (XXXVI,H3.1K27M), SU-DIPG-XIII (XIII, H3.3K27M) and SU-DIPG-XVII (XVII, H3.3K27M) cell lines were generously provided by the laboratory of M. Monje (Stanford University) and have been previously described(Grasso et al, 2015). The high grade glioma (HGG) cell line with wildtype histone genes VUMC-DIPG-10 (VUMC)(Meel et al, 2017) was obtained through a materials transfer agreement with Esther Hulleman (VU University Medical Center, Amsterdam, Netherlands), and generation of PBT-04 was reported previously (PBT; Brabetz et al, 2018).The H1 ESC line was obtained from WiCell (Madison WI). The U5 neural stem cell (NSC) line(Toledo et al, 2015) was obtained from PJ Paddison (FHCRC, Seattle WA).…”

mentioning

confidence: 99%

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

Sarthy

Janssens

Henikoff

et al. 2020

eLife

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Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

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Culture methods of diffuse intrinsic pontine glioma cells determine response to targeted therapies

Cited by 26 publications

References 42 publications

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

Hypoxic Environment and Paired Hierarchical 3D and 2D Models of Pediatric H3.3-Mutated Gliomas Recreate the Patient Tumor Complexity

Signaling pathways and mesenchymal transition in pediatric high-grade glioma

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones

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