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Glioblastoma is the most lethal primary malignant brain tumor in adults. Simplified two-dimensional (2D) cell culture and neurospheres in vitro models fail to recapitulate the complexity of the tumor microenvironment, limiting its ability to predict therapeutic response. Three-dimensional (3D) scaffold-based models have emerged as a promising alternative for addressing these concerns. One such 3D system is gelatin methacrylate (GelMA) hydrogels, and we aimed to understand the suitability of using this system to mimic treatment-resistant glioblastoma cells that reside in specific niches. We characterized the phenotype of patient-derived glioma cells cultured in GelMA hydrogels (3D-GMH) for their tumorigenic properties using invasion and chemoresponse assays. In addition, we used integrated single-cell and spatial transcriptome analysis to compare cells cultured in 3D-GMH to neoplastic cells in vivo. Finally, we assessed tumor-immune cell interactions with a macrophage infiltration assay and a cytokine array. We show that the 3D-GMH system enriches treatment-resistant mesenchymal cells that are not represented in neurosphere cultures. Cells cultured in 3D-GMH resemble a mesenchymal-like cellular phenotype found in perivascular and hypoxic regions and recruit macrophages by secreting cytokines, a hallmark of the mesenchymal phenotype. Our 3D-GMH model effectively mimics the phenotype of glioma cells that are found in the perivascular and hypoxic niches of the glioblastoma core in situ, in contrast to the neurosphere cultures that enrich cells of the infiltrative edge of the tumor. This contrast highlights the need for due diligence in selecting an appropriate model when designing a study‘s objectives.

Background Human endogenous retroviruses (HERVs) are remnants of ancient viral infections and comprise 6–8% of the human genome. Their biological functions in cancer remain poorly understood, especially in glioblastoma, the most common and deadly primary brain cancer in adults. Prior studies on HERV expression in glioblastoma have yielded conflicting results. Here, we employed orthogonal computational pipelines to address these limitations. Results Locus-specific analysis revealed marked heterogeneity of transcription among HERVs within the same clade. We found that individual HERV proviruses are more than twice as likely to be underexpressed in glioblastoma than overexpressed and that most differentially expressed HERVs are exonized within transcripts. These HERVs are enriched in the 3’-terminal exons of transcripts, associated with alternative polyadenylation and contribute conserved polyadenylation signals. We identified HERV expression patterns associated with glioblastoma subtypes and anatomic features. We also identified three proviruses or proviral fragments of particular interest including one associated with survival and one exonized within a currently unannotated cancer-specific transcript. Among the most recently integrated clade of HERVs, excluding solo-LTRs, only the HML-2 provirus at 1q22 is overexpressed in glioblastoma. We report previously undescribed transcripts incorporating this provirus that may encode several proteins. Conclusions This study represents the first systematic exploration of the heterogeneity of HERV expression between anatomic features of any cancer. It shows that exaptation of HERV polyadenylation signals and HERV-associated APA are widespread in the human transcriptome and identifies critical structural information regarding the HML-2 1q22 provirus transcript, which has been the focus of several recent analyses. Our findings underscore the importance of locus-specific and anatomic feature-specific HERV analysis and suggest structural and functional roles for HERVs in glioblastoma-associated transcripts.

Glioblastoma is the most lethal form of human brain cancer. The genomic alterations and gene expression profiles characterizing this tumor type have been widely studied. Puchalski et al. created the Ivy Glioblastoma Atlas, a freely available online resource for the research community. The atlas, a collaborative effort between bioinformaticians and pathologists, maps molecular features of glioblastomas, such as transcriptional signatures, to histologically defined anatomical regions of the tumors. The relationships identified in this atlas, in conjunction with associated databases of clinical and genomic information, could provide new insights into the pathogenesis, diagnosis, and treatment of glioblastoma. Science , this issue p. 660 An online resource maps the molecular genetic features of glioblastoma, a lethal brain cancer, to its anatomic features. Glioblastoma is an aggressive brain tumor that carries a poor prognosis. The tumor’s molecular and cellular landscapes are complex, and their relationships to histologic features routinely used for diagnosis are unclear. We present the Ivy Glioblastoma Atlas, an anatomically based transcriptional atlas of human glioblastoma that aligns individual histologic features with genomic alterations and gene expression patterns, thus assigning molecular information to the most important morphologic hallmarks of the tumor. The atlas and its clinical and genomic database are freely accessible online data resources that will serve as a valuable platform for future investigations of glioblastoma pathogenesis, diagnosis, and treatment.

Radial glia (RG) are primarily embryonic neuroglial progenitors that express Brain Lipid Binding Protein (Blbp a.k.a. Fabp7) and Glial Fibrillary Acidic Protein (Gfap). We used these transcripts to demarcate the distribution of spinal cord radial glia (SCRG) and screen for SCRG gene expression in the Allen Spinal Cord Atlas (ASCA). We reveal that neonatal and adult SCRG are anchored in a non-ventricular niche at the spinal cord (SC) pial boundary, and express a \"signature\" subset of 122 genes, many of which are shared with \"classic\" neural stem cells (NSCs) of the subventricular zone (SVZ) and SC central canal (CC). A core expressed gene set shared between SCRG and progenitors of the SVZ and CC is particularly enriched in genes associated with human disease. Visualizing SCRG in a Fabp7-EGFP reporter mouse reveals an extensive population of SCRG that extend processes around the SC boundary and inwardly (through) the SC white matter (WM), whose abundance increases in a gradient from cervical to lumbar SC. Confocal analysis of multiple NSC-enriched proteins reveals that postnatal SCRG are a discrete and heterogeneous potential progenitor population that become activated by multiple SC lesions, and that CC progenitors are also more heterogeneous than previously appreciated. Gene ontology analysis highlights potentially unique regulatory pathways that may be further manipulated in SCRG to enhance repair in the context of injury and SC disease.

The Sac (saccharin preference) locus affecting mouse behavioral and neural responsiveness to sweeteners has been mapped to distal Chr 4. A putative sweet taste receptor, T1R1, has been recently cloned, and the gene encoding it, Gpr70, has also been mapped to mouse distal Chr 4. To assess Gpr70 as a candidate gene for Sac, we compared the Gpr70 sequences of C57BL/6ByJ and 129P3/J mouse strains with different alleles of Sac. Using Gpr70 sequence variation between the C57BL/6ByJ and 129P3/J strains, we conducted a high-resolution analysis of the chromosomal localization of the Gpr70 and Sac loci in the F2 hybrids and 129.B6-Sac partially congenic mice originating from these two strains. The Gpr70 gene maps proximal to Sac, which demonstrates that they are different loci.

Purpose For glioblastoma (GBM), imaging response (IR) or pseudoprogression (PSP) is frequently observed after chemoradiation and may connote a favorable prognosis. With tumors categorized by the Cancer Genome Atlas Project (mesenchymal, classical, neural, and proneural) and by methylguanine-methyltransferase (MGMT) methylation status, we attempted to determine if certain genomic or molecular subtypes of GBM were specifically associated with IR or PSP. Methods Patients with GBM treated at two institutions were reviewed. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Mantel-cox test determined effect of IR and PSP on OS and PFS. Fisher’s exact test was utilized to correlate IR and PSP with genomic subtypes and MGMT status. Results Eighty-two patients with GBM were reviewed. The median OS and PFS were 17.9 months and 8.9 months. IR was observed in 28 (40%) and was associated with improved OS (median 29.4 vs 14.5 months p  < 0.01) and PFS (median 17.7 vs 5.5 months, p  < 0.01). PSP was observed in 14 (19.2%) and trended towards improved PFS (15.0 vs 7.7 months p  = 0.08). Tumors with a proneural component had a higher rate of IR compared to those without a proneural component (IR 60% vs 28%; p  = 0.03). MGMT methylation was associated with IR (58% vs 24%, p  = 0.032), but not PSP (34%, p  = 0.10). Conclusion IR is associated with improved OS and PFS. The proneural subtype and MGMT methylated tumors had higher rates of IR.

Molecular approaches to understanding the functional circuitry of the nervous system promise new insights into the relationship between genes, brain and behaviour. The cellular diversity of the brain necessitates a cellular resolution approach towards understanding the functional genomics of the nervous system. We describe here an anatomically comprehensive digital atlas containing the expression patterns of ∼20,000 genes in the adult mouse brain. Data were generated using automated high-throughput procedures for in situ hybridization and data acquisition, and are publicly accessible online. Newly developed image-based informatics tools allow global genome-scale structural analysis and cross-correlation, as well as identification of regionally enriched genes. Unbiased fine-resolution analysis has identified highly specific cellular markers as well as extensive evidence of cellular heterogeneity not evident in classical neuroanatomical atlases. This highly standardized atlas provides an open, primary data resource for a wide variety of further studies concerning brain organization and function. Brain bank A new frontier has been reached in both neuroscience and genetics. The expression of each of the roughly 22,000 genes of the mouse genome has been mapped, at cellular resolution, across all major structures of the mouse brain. This achievement is part of the Allen Brain Atlas project. Lein et al . describe the development of the atlas (freely available on http://www.brain-map.org ) and report gene expression patterns that both support and challenge established views of brain anatomy. The atlas includes in situ images and 'heat maps' of signal intensity for each gene and brain region on a colorimetric scale. Despite predictions that the brain would express a limited number of genes, about 80% of all mouse genes are expressed; 70% of gene signals localize to fewer than 20% of all brain cells, suggesting that most localize to small brain regions. Cover image: Chris Lau, Allen Institute for Brain Science. The expression of each of the roughly 22,000 genes of the mouse genome has been mapped, at cellular resolution, across all major structures of the mouse brain, revealing that 80% of all genes appear to be expressed in the brain.

Glioblastoma is the most lethal primary malignant brain tumor in adults. Simplified two-dimensional(2D) cell culture and neurospheres in vitro models fail to recapitulate the complexity of the tumor microenvironment, limiting its ability to predict therapeutic response. Three-dimensional(3D) scaffold-based models have emerged as a promising alternative for addressing these concerns. One such 3D system is gelatin methacrylate(GelMA) hydrogels, which can be used for modeling the glioblastoma microenvironment. We characterized the phenotype of patient-derived glioma cells cultured in GelMA hydrogels(3D-GMH) for their tumorigenic properties using invasion and chemoresponse assays. In addition, we used integrated single-cell and spatial transcriptome analysis to compare cells cultured in 3D-GMH to cells in vivo. Finally, we assessed tumor-immune cell interactions with a macrophage infiltration assay and a cytokine array. We show that cells cultured in 3D-GMH develop a mesenchymal-like cellular phenotype found in perivascular and hypoxic regions present in the core of the tumor, and recruit macrophages by secreting cytokines in contrast to the cells grown as neurospheres that match the phenotype of cells of the infiltrative edge of the tumor.