New <i>in vivo</i> avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis

Plessier, Alexandre; Ledret, Ludivine; Varlet, Pascale; Beccaria, Kévin; Lacombe, J.; Mériaux, Sébastien; Geffroy, Françoise; Fiette, Laurence; Flamant, Patricia; Chrétien, Fabrice; Blauwblomme, Thomas; Puget, Stéphanie; Grill, Jacques; Debily, Marie‐Anne; Castel, David

doi:10.18632/oncotarget.15002

Cited by 41 publications

(39 citation statements)

References 35 publications

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“…These findings suggest that DIPG cells follow preferential routes for dissemination along pre-existing structures, or are guided by signaling molecules from specific niches in order to invade distal sites, which is a well-established concept for cancer metastasis (84). Pericellular and axonal location of DIPG cells in patient-derived xenograph models that strongly recapitulate human disease (79), suggest that tumor cells use neural cell stands as railways to migrate through the brain. This trait could be reminiscent of neuroblasts that use radial glial fibers as migratory tracks to guide them during embryonic brain development (85,86).…”

Section: Dipg Follows Preferred Routes For Invasionmentioning

confidence: 88%

“…Most importantly, as mentioned before, although DIPG and GBM are genetically and molecularly distinct diseases (14), most DIPG trials have focused on drugs that were seen effective in GBM (13), overlooking the specifics of DIPG pathology. This also results from a lack in suitable experimental models for DIPG that take into account its specific spatiotemporal and often relatively slow progression in the developing brain (79). In part because of practical reasons, fast growing, high proliferative models are often used, which might not adequately reflect tumor behavior in patients.…”

Section: Therapeutic Targeting Of Dipg Invasionmentioning

confidence: 99%

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Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

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Diffuse Intrinsic Pontine Glioma (DIPG) is a rare, highly aggressive pediatric brain tumor that originates in the pons. DIPG is untreatable and universally fatal, with a median life expectancy of less than a year. Resection is not an option, due to the anatomical location of the tumor, radiotherapy has limited effect and no chemotherapeutic or targeted treatment approach has proven to be successful. This poor prognosis is partly attributed to the tumor's highly infiltrative diffuse and invasive spread. Thus, targeting the invasive behavior of DIPG has the potential to be of therapeutic value. In order to target DIPG invasion successfully, detailed mechanistic knowledge on the underlying drivers is required. Here, we review both DIPG tumor cell's intrinsic molecular processes and extrinsic environmental factors contributing to DIPG invasion. Importantly, DIPG represents a heterogenous disease and through advances in whole-genome sequencing, different subtypes of disease based on underlying driver mutations are now being recognized. Recent evidence also demonstrates intra-tumor heterogeneity in terms of invasiveness and implies that highly infiltrative tumor subclones can enhance the migratory behavior of neighboring cells. This might partially be mediated by "tumor microtubes," long membranous extensions through which tumor cells connect and communicate, as well as through the secretion of extracellular vesicles. Some of the described processes involved in invasion are already being targeted in clinical trials. However, more research into the mechanisms of DIPG invasion is urgently needed and might result in the development of an effective therapy for children suffering from this devastating disease. We discuss the implications of newly discovered invasive mechanisms for therapeutic targeting and the challenges therapy development face in light of disease in the developing brain.

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Section: Dipg Follows Preferred Routes For Invasionmentioning

confidence: 88%

Section: Therapeutic Targeting Of Dipg Invasionmentioning

confidence: 99%

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

et al. 2020

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“…Glioma stem-like cells (GSC) derived from stereotactic biopsies at diagnosis (19). Control human neural stem cells hNSC1 were from commercial origin (Applied Stem Cells, ASE-5001), and hNSC2-3 were derived from human embryo of Carnegie stages 18 and 22 obtained following voluntary abortions (20).…”

Section: Cells and Culturementioning

confidence: 99%

“…In order to decipher the underlying molecular basis of the variable clinical response of DIPG patients to RT, we assessed the cellular consequences of IR in vitro using DIPG cellular models deriving from primary tumors at diagnosis (19). We could not perform in all cell cultures classical clonogenic assays commonly used to evaluate radiosensitivity.…”

Section: Distribution Of Dipg Stem Cells' Radiosensitivity In Vitromentioning

confidence: 99%

TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)

Werbrouck

Evangelista

Lobón-Iglesias

et al. 2019

Clinical Cancer Research

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Purpose: Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG. Experimental Design: We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-na€ ve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations. Results: We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53 WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53 MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53 WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53 MUT cells. Conclusions: Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.

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“…In 2012, the identification of histone mutations (K27M in H3F3A, HIST1H3B/C and HIST2H3A/C genes) was a major breakthrough in the knowledge of this disease (10,23,31,42). It led to the recognition of a new entity called "diffuse midline glioma, H3K27M-mutant" in the latest WHO Classification of Central Nervous System Tumors (41).…”

Section: Introductionmentioning

confidence: 99%

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

et al. 2019

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Pediatric diffuse midline gliomas are devastating diseases. Among them, diffuse midline gliomas H3K27M-mutant are associated with worse prognosis. However, recent studies have highlighted significant differences in clinical behavior and biological alterations within this specific subgroup. In this context, simple markers are needed to refine the prognosis of diffuse midline gliomas H3K27M-mutant and guide the clinical management of patients. The aims of this study were (i) to describe the molecular, immunohistochemical and, especially, chromosomal features of a cohort of diffuse midline gliomas and (ii) to focus on H3K27M-mutant tumors to identify new prognostic markers. Patients were retrospectively selected from 2001 to 2017. Tumor samples were analyzed by immunohistochemistry (including H3K27me3, EGFR, c-MET and p53), next-generation sequencing and comparative genomic hybridization array. Forty-nine patients were included in the study. The median age at diagnosis was 9 years, and the median overall survival (OS) was 9.4 months. H3F3A or HIST1H3B mutations were identified in 80% of the samples. Within the H3K27M-mutant tumors, PDGFRA amplification, loss of 17p and a complex chromosomal profile were significantly associated with worse survival. Three prognostic markers were identified in diffuse midline gliomas H3K27M-mutant: PDGFRA amplification, loss of 17p and a complex chromosomal profile. These markers are easy to detect in daily practice and should be considered to refine the prognosis of this entity.Dufour et al Prognostic markers in diffuse gliomas H3K27M-mutant Brain Pathology 30 (2020) [179][180][181][182][183][184][185][186][187][188][189][190]

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New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis

Cited by 41 publications

References 35 publications

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

Invaders Exposed: Understanding and Targeting Tumor Cell Invasion in Diffuse Intrinsic Pontine Glioma

TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)

Identification of prognostic markers in diffuse midline gliomas H3K27M‐mutant

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