Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma

Abstract

Pediatric GBM harbors genetic subclones that rapidly evolve at recurrence. Patientparents trios reveal de novo germline variants in pGBM patients.

Integration of Multiple Platforms for the Analysis of Multifluorescent Marking Technology Applied to Pediatric GBM and DIPG

“…A significant degree of genetic and phenotypic intratumor heterogeneity has been recently identified in pGBM and DIPG, which may represent one of the most challenging aspect in the effort to develop new effective therapeutic strategies for these diseases [ 8 , 9 , 10 , 11 , 12 ]. It has been shown that they are characterized by temporal and spatial intratumoral genomic heterogeneity, which rapidly evolves following surgical and chemotherapy treatment.…”

Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

“…In fact, aHGG are mainly located in hemispheres, whereas pHGG are frequently located in midline brainstem and thalamic structures. As already mentioned, O 2 tensions and hypoxic niches are not directly located in those brain areas [21,23,34,35,43]. Nevertheless, both aHGG and pHGG invade the SVZ at the end of their evolution with differences in the invasive process under the pressure of hypoxic regions and gene deregulations [36].…”

“…The study of Castel et al associated this pro-angiogenic signature to H3.1 K27M mutated tumors, but other studies Despite these contradictory results between SVZ and local hypoxia, it appears that physiological neural stem cells benefit from hypoxic conditions in a healthy brain and are thus capable of self-renewing to give birth to neural cells that migrate while differentiating into mature and functional neurons. Probably, these normal stem cell capacities in hypoxic niches are also used by pHGG stem cells, leading to an even more complex HGG hypoxic environment, unlimited and slow self-renewal and a high propensity to migrate rapidly [43]. This can also explain why a really frequent invasive terminal process in this SVZ is present during pHGG progression.…”

Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

“…The location of GBM is a significant barrier to successful treatment. As well as making surgical resection difficult, the extracellular matrix (ECM) composition [ 23 , 24 ], tissue mechanics [ 15 , 25 ] and stromal-cell interactions [ 26 , 27 , 28 ] within the brain elicit unique tumour qualities. The brain provides tissue niches for stem-like cancer stem cells (CSC s ) and hypoxic regions develop, which further enables drug resistance and recurrence [ 29 , 30 ].…”

“…Mouse orthotopic xenografts of patient-derived cells display genetic heterogeneity [ 24 ] and patient-specific drug responses [ 69 ] and responses to fluid shear [ 70 ] and thus provide disease relevance. Pepin et al found that IDH1 -mutated PDX GBM models were significantly softer than wild-type GBM via MRE [ 63 ].…”