Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma.

Glioblastoma multiforme (GBM) is a highly lethal human cancer thought to originate from a self-renewing and therapeutically-resistant population of glioblastoma stem cells (GSCs). The intrinsic mechanisms enacted by GSCs during 3D tumor formation, however, remain unclear, especially in the stages prior to angiogenic/immunological infiltration. In this study, we performed a deep characterization of the genetic, immune, and metabolic profiles of GBM organoids from several patient-derived GSCs (GBMO). Despite being devoid of immune cells, transcriptomic analysis across GBMO revealed a surprising immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We find two important cell populations thought to drive GBM progression, Special AT-rich sequence-binding protein 2 (SATB2+) and homeodomain-only protein homeobox (HOPX+) progenitors, contribute to this immune landscape in GBMO and GBM in vivo. These progenitors, but not other cell types in GBMO, are resistant to conventional GBM therapies, temozolomide and irradiation. Our work defines a novel intrinsic immune-like landscape in GBMO driven, in part, by SATB2+ and HOPX+ progenitors and deepens our understanding of the intrinsic mechanisms utilized by GSCs in early GBM formation.

Stat1 is an inducible transcriptional repressor of neural stem cells self-renewal program during neuroinflammation.

A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of endogenous stem cells in response to injury and disease. Interferons increase hematopoietic stem cells during infection by activating STAT1, but the mechanisms by which STAT1 regulates intrinsic programs in neural stem cells (NSCs) during neuroinflammation is less known. Here we explored the role of STAT1 on NSC self-renewal. We show that overexpressing Stat1 in NSCs derived from the subventricular zone (SVZ) decreases NSC self-renewal capacity while Stat1 deletion increases NSC self-renewal, neurogenesis, and oligodendrogenesis in isolated NSCs. Importantly, we find upregulation of STAT1 in NSCs in a mouse model of multiple sclerosis (MS) and an increase in pathological T cells expressing IFN-γ rather than interleukin 17 (IL-17) in the cerebrospinal fluid of affected mice. We find IFN-γ is superior to IL-17 in reducing proliferation and precipitating an abnormal NSC phenotype featuring increased STAT1 phosphorylation and Stat1 and p16ink4a gene expression. Notably, Stat1-/- NSCs were resistant to the effect of IFN-γ. Lastly, we identified a Stat1-dependent gene expression profile associated with an increase in the Sox9 transcription factor, a regulator of self-renewal. Stat1 binds and transcriptionally represses Sox9 in a transcriptional luciferase assay. We conclude that Stat1 serves as an inducible checkpoint for NSC self-renewal that is upregulated during chronic brain inflammation leading to decreased self-renewal. As such, Stat1 may be a potential target to modulate for next generation therapies to prevent progression and loss of repair function in NSCs/neural progenitors in MS.

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

Venous thromboembolism in children with central nervous system tumors: Comparison of an institutional cohort to a national administrative database.

BACKGROUND: Central nervous system (CNS) tumors are the second most common malignancy of childhood, and published data on venous thromboembolism (VTE) rate and risk factors for these patients are outdated or incomplete. Here, we determine the cumulative incidence and risk factors for VTE in this population. PROCEDURE: VTE diagnosis and associated clinical risk factors were abstracted and analyzed for two cohorts of children (0-21 years) diagnosed with CNS tumors between January 1, 2010 to September 30, 2018. The first study was a retrospective single institution cohort study. The initial observations were confirmed across multiple pediatric hospitals using the Pediatric Health Information System (PHIS) administrative database. RESULTS: The single-institution cohort included 338 patients aged 3 days to 20.9 years (median age, 8.6 years); VTE developed in eight (2.4%) patients. The PHIS cohort included 17 634 patients aged from 0 to 21.9 years (median: 9.5 years); VTE developed in 354 (2.0%) patients. Univariate analysis for the single-institution cohort identified central venous catheter (CVC) placement as a risk factor for VTE (odds ratio [OR] 8.40, 95% confidence interval [CI] 1.43-49.41, P = .0186). Multivariable analysis of the PHIS dataset identified CVC placement (OR 1.97, 95% CI 1.57-2.46; P < .0001), obesity (OR 2.96, 95% CI 1.21-7.26; P = .0177), and more than one hospital admission (OR 3.54, 95% CI 2.69-4.64; P < .0001) as significant predictors of VTE. VTE diagnosis was not associated with increased mortality in either cohort. CONCLUSIONS: The VTE rate in children with CNS tumors is low (2%). CVC placement was identified as a modifiable risk factor in both cohorts.

Convergence of human cellular models and genetics to study neural stem cell signaling to enhance central nervous system regeneration and repair.

Human central nervous system (CNS) regeneration is considered the holy grail of neuroscience research, and is one of the most pressing and difficult questions in biology and science. Despite more than 20 years of work in the field of neural stem cells (NSCs), the area remains in its infancy as our understanding of the fundamental mechanisms that can be leveraged to improve CNS regeneration in neurological diseases is still growing. Here, we focus on the recent lessons from lower organism CNS regeneration genetics and how such findings are starting to illuminate our understanding of NSC signaling pathways in humans. These findings will allow us to improve upon our knowledge of endogenous NSC function, the utility of exogenous NSCs, and the limitations of NSCs as therapeutic vehicles for providing relief from devastating human neurological diseases. We also discuss the limitations of activating NSC signaling for CNS repair in humans, especially the potential for tumor formation. Finally, we will review the recent advances in new culture techniques, including patient-derived cells and cerebral organoids to model the genetic regulation of signaling pathways controlling the function of NSCs during injury and disease states.