Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.

Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell-state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment.

An atlas of causal and mechanistic drivers of interpatient heterogeneity in glioma.

Grade IV glioma, formerly known as glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging in part due to extensive interpatient heterogeneity in disease driving mechanisms and lack of prognostic and predictive biomarkers. Using mechanistic inference of node-edge relationship (MINER), we have analyzed multiomics profiles from 516 patients and constructed an atlas of causal and mechanistic drivers of interpatient heterogeneity in GBM (gbmMINER). The atlas has delineated how 30 driver mutations act in a combinatorial scheme to causally influence a network of regulators (306 transcription factors and 73 miRNAs) of 179 transcriptional "programs", influencing disease progression in patients across 23 disease states.

Gene regulatory network topology governs resistance and treatment escape in glioma stem-like cells.

Poor prognosis and drug resistance in glioblastoma (GBM) can result from cellular heterogeneity and treatment-induced shifts in phenotypic states of tumor cells, including dedifferentiation into glioma stem-like cells (GSCs). This rare tumorigenic cell subpopulation resists temozolomide, undergoes proneural-to-mesenchymal transition (PMT) to evade therapy, and drives recurrence. Through inference of transcriptional regulatory networks (TRNs) of patient-derived GSCs (PD-GSCs) at single-cell resolution, we demonstrate how the topology of transcription factor interaction networks drives distinct trajectories of cell state transitions in PD-GSCs resistant or susceptible to cytotoxic drug treatment.

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex.

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1.

Interindividual variation in human cortical cell type abundance and expression.

Single-cell transcriptomic studies have identified a conserved set of neocortical cell types from small postmortem cohorts. We extended these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in the middle temporal gyrus.

An expanded safety/feasibility study of the EMulate Therapeutics Voyager™ System in patients with recurrent glioblastoma.

The EMulate Therapeutics Voyager™ is a simple, wearable, home-use device that uses an alternating electromagnetic field to alter biologic signaling within cells. To assess the safety/feasibility of the Voyager in the treatment of recurrent glioblastoma (rGBM). In this study, patients with rGBM were treated with Voyager as monotherapy or in combination with standard chemotherapy at the Investigator's discretion.

The potential role of human endogenous retrovirus K in glioblastoma.

The most active human endogenous retrovirus K (HERV-K) subtype, HML-2, has been implicated as a driver of oncogenesis in several cancers. However, the presence and function of HML-2 in malignant gliomas has remained unclear. In this issue of the JCI, Shah and colleagues demonstrate HML-2 overexpression in glioblastoma (GBM) and its role in maintaining the cancer stem cell phenotype.

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex.

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial.

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.

Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.

Agent-based computational modeling of glioblastoma predicts that stromal density is central to oncolytic virus efficacy.

Oncolytic viruses (OVs) are emerging cancer immunotherapy. Despite notable successes in the treatment of some tumors, OV therapy for central nervous system cancers has failed to show efficacy. We used an tumor model developed from human glioblastoma tissue to evaluate the infiltration of herpes simplex OV rQNestin (oHSV-1) into glioblastoma tumors.

Human neocortical expansion involves glutamatergic neuron diversification.

The neocortex is disproportionately expanded in human compared with mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues.

Signature morpho-electric, transcriptomic, and dendritic properties of human layer 5 neocortical pyramidal neurons.

In the neocortex, subcerebral axonal projections originate largely from layer 5 (L5) extratelencephalic-projecting (ET) neurons. The unique morpho-electric properties of these neurons have been mainly described in rodents, where retrograde tracers or transgenic lines can label them. Similar labeling strategies are infeasible in the human neocortex, rendering the translational relevance of findings in rodents unclear.

Detection of Human Papillomavirus Integration in Brain Metastases from Oropharyngeal Tumors by Targeted Sequencing.

Human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC) are known to have differential phenotypes, including the incidence and location of metastases. HPV positive (HPV+) HNSCC are more likely to metastasize to distant sites, such as the lung, brain, and skin. Among these locations, metastasis to the brain is a rare event, and little is known about specific risk factors for this phenotype.

A Systems Approach to Brain Tumor Treatment.

Brain tumors are among the most lethal tumors. Glioblastoma, the most frequent primary brain tumor in adults, has a median survival time of approximately 15 months after diagnosis or a five-year survival rate of 10%; the recurrence rate is nearly 90%. Unfortunately, this prognosis has not improved for several decades.

Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex.

Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse.

Glioma Stem Cells as Immunotherapeutic Targets: Advancements and Challenges.

Glioblastoma is the most common and lethal primary brain malignancy. Despite major investments in research into glioblastoma biology and drug development, treatment remains limited and survival has not substantially improved beyond 1-2 years. Cancer stem cells (CSC) or glioma stem cells (GSC) refer to a population of tumor originating cells capable of self-renewal and differentiation.

Low-Grade Gemistocytic Morphology in H3 G34R-Mutant Gliomas and Concurrent K27M Mutation: Clinicopathologic Findings.

Mutations in histone H3 are key molecular drivers of pediatric and young adult high-grade gliomas. Histone H3 G34R mutations occur in hemispheric high-grade gliomas and H3 K27M mutations occur in aggressive, though histologically diverse, midline gliomas. Here, we report 2 rare cases of histologically low-grade gliomas with gemistocytic morphology and sequencing-confirmed histone H3 G34R mutations.

Human cytomegalovirus seropositivity is associated with decreased survival in glioblastoma patients.

Background: Human cytomegalovirus (HCMV) is an oncomodulatory human herpesvirus that has been detected in glioblastoma (GBM) and is associated with worse prognosis in patients with the disease. The effects of HCMV systemic infection on survival in GBM patients, however, are largely unknown. We aimed to determine the association between HCMV serostatus at diagnosis and survival via a retrospective cohort study of GBM patients.

PHIP drives glioblastoma motility and invasion by regulating the focal adhesion complex.

The invasive behavior of glioblastoma is essential to its aggressive potential. Here, we show that pleckstrin homology domain interacting protein (PHIP), acting through effects on the force transduction layer of the focal adhesion complex, drives glioblastoma motility and invasion. Immunofluorescence analysis localized PHIP to the leading edge of glioblastoma cells, together with several focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phosphorylated forms of paxillin (pPXN) and focal adhesion kinase (pFAK).

Transcriptomic evidence that von Economo neurons are regionally specialized extratelencephalic-projecting excitatory neurons.

von Economo neurons (VENs) are bipolar, spindle-shaped neurons restricted to layer 5 of human frontoinsula and anterior cingulate cortex that appear to be selectively vulnerable to neuropsychiatric and neurodegenerative diseases, although little is known about other VEN cellular phenotypes. Single nucleus RNA-sequencing of frontoinsula layer 5 identifies a transcriptomically-defined cell cluster that contained VENs, but also fork cells and a subset of pyramidal neurons. Cross-species alignment of this cell cluster with a well-annotated mouse classification shows strong homology to extratelencephalic (ET) excitatory neurons that project to subcerebral targets.

Cytomegalovirus is a tumor-associated virus: armed and dangerous.

Human cytomegalovirus (HCMV) gene products are present in multiple human malignancies, often in specific association with tumor cells and tumor vasculature. Emerging evidence from human and mouse models of CMV infection in cancer indicate that CMV can transform epithelial cells, promote epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial (MET) in tumor cells, promote tumor angiogenesis and proliferation and incapacitate the host anti-CMV immune response. This review will discuss the increasing role of HCMV in human cancer by demonstrating how HCMV is well suited for impacting major themes in oncogenesis including initiation, promotion, progression, metastasis and immune evasion.

Conserved cell types with divergent features in human versus mouse cortex.

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected.