The importance of integrating surgical resection into preclinical glioblastoma modeling.

Glioblastoma remains a challenging tumor in terms of clinical management with limited progress made since the standard of care was established in 2005. Maximal safe surgical resection, a cornerstone of the standard of care regimen, is a major determinant in patient outcome. However, this key clinical parameter is generally not accounted for in preclinical models, which are often used to provide a rationale for early phase clinical trials.

The Lipid Hydrolase ABHD6 is a Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Related Hepatocellular Carcinoma.

Unlabelled: Primary liver cancer accounts for approximately 700,000 deaths worldwide annually ranking third in cancer-related mortality, with hepatocellular carcinoma (HCC) comprising the majority of these tumors. Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a leading cause of HCC in the United States. We previously identified the lipid hydrolase alpha/beta hydrolase domain 6 (ABHD6) as a key mediator of the development of metabolic syndrome and intimately involved in cell signaling, making it a prime target for investigation in MASLD-related HCC.

Immunotherapy in Glioblastoma: An Overview of Current Status.

Glioblastoma (GB) is an aggressive brain tumor with standard therapies offering limited but measurable survival benefit. Immunotherapy is expanding the treatment landscape for GB. Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have shown benefit in several cancers and are being studied in GB, with ongoing efforts to address the tumor's immunosuppressive environment.

Glycoprotein NMB mediates bidirectional GSC-TAM interactions to promote tumor progression.

Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of GBM stem cells (GSCs) that interaction with surrounding cells, including infiltrating tumor-associated macrophages and microglia (TAMs). While GSCs and TAMs are in close proximity and likely interact to coordinate tumor growth, a limited number of mechanisms have been identified that support their communication. Here, we identified glycoprotein NMB (GPNMB) as a key factor mediating a unique bidirectional interaction between GSCs and TAMs in GBM.

Connexin43 functions as a non-canonical phenotypic stability factor in promoting hybrid Epithelial/Mesenchymal phenotype in glioblastoma cells.

Glioblastoma (GBM) is a highly malignant and aggressive brain tumor with patients typically experiencing a median survival of 15-18 months after diagnosis. Gap junction protein Connexin43 (Cx43) plays a crucial role in GBM by having both tumor-suppressing and tumor-promoting roles. Here, we identify a critical tumor-promoting role of Cx43 in GBM by functioning as a non-canonical phenotypic stability factor and driving partial EMT, which enhances the acquisition of stemness properties in the cells.

Bioprinting of GelMA-Based Hydrogels to Aid in Creation of Biomimetic 3D Models for Glioblastoma.

Glioblastoma (GBM, isocitrate dehydrogenase wild-type) is the most common primary malignant brain tumor in adults and is associated with a severely low survival rate. Treatments offer mere palliation and are ineffective, due, in part, to a lack of understanding of the intricate mechanisms underlying the disease, including the contribution of the tumor microenvironment (TME). Current GBM models continue to face challenges as they lack the critical components and properties required.

Leveraging dysregulated tumor metabolism for targeting anticancer bacteria.

Widespread application of bacterial-based cancer therapy is limited because of the need to increase therapeutic bacteria specificity to the tumor to improve treatment safety and efficacy. Here, we harness the altered tumor metabolism and specifically elevated kynurenine accumulation to target engineered bacteria to the cancer site. We cloned and leveraged kynurenine-responsive transcriptional regulator (KynR) with its cognate promoter in .

Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models.

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3β/STAT3 pathway.

A Material Transfer Agreement between Glioblastoma and Normal Brain Cells.

Tumor cells communicate with normal cells in various ways, typically leading to the exploitation of resources of the normal cells by tumor cells for their benefit. In this issue, Mangena and colleagues use three-dimensional organoid models to show the transfer of GFP and mRNA from malignant glioblastoma to nonmalignant cells in cerebral organoid models; this transfer is facilitated by extracellular vesicles and possibly tunneling nanotubes, demonstrating how nonmalignant cells in the tumor microenvironment can be exploited by neighboring malignant cells. See related article by Mangena et al.

VTE incidence shortens survival in IDH-WT glioblastoma.

Background: Venous thromboembolisms (VTE's) are the second leading cause of death in cancer patients. While previous analyses have demonstrated VTE rates are greater in GBM patients using smaller patient cohorts in high-grade glioma, since the release of the update 5 edition of the World Health Organization (WHO) classification a systematic analysis in a large-scale cohort of patients with IDH-wildtype GBM with clinical outcomes is lacking.

Methods: This study utilizes the online database, TriNetx, to build patient cohorts for outcomes analysis.

miR-644a is a tumor cell-intrinsic mediator of sex bias in glioblastoma.

Background: Biological sex is an important risk factor for glioblastoma (GBM), with males having a higher incidence and poorer prognosis. The mechanisms for this sex bias are thought to be both tumor intrinsic and tumor extrinsic. MicroRNAs (miRNAs), key posttranscriptional regulators of gene expression, have been previously linked to sex differences in various cell types and diseases, but their role in the sex bias of GBM remains unknown.

Tumor cell-derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment.

Immunotherapy for glioblastoma: current state, challenges, and future perspectives.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers.

Circulating Gut Microbe-Derived Metabolites Are Associated with Hepatocellular Carcinoma.

Unlabelled: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites.

Macrophage migration inhibitory factor as a therapeutic target in neuro-oncology: A review.

Primary central nervous system (CNS) tumors affect tens of thousands of patients each year, and there is a significant need for new treatments. Macrophage migration inhibitory factor (MIF) is a cytokine implicated in multiple tumorigenic processes such as cell proliferation, vascularization, and immune evasion and is therefore a promising therapeutic target in primary CNS tumors. There are several MIF-directed treatments available, including small-molecule inhibitors, peptide drugs, and monoclonal antibodies.

Journey through tumorverse: Creating models to decode PXA mysteries.

Pleomorphic xanthoastrocytoma (PXA) is a rare pediatric low-grade glioma (pLGG), of which 60%-80% exhibit the BRAF V600E mutation, that enhances the aggressiveness and progression to an eventual pediatric high-grade glioma (pHGG). Despite the aggressiveness of this mutational status, the mechanisms underlying the progression of BRAF V600E tumors remain poorly understood, primarily due to limited insights into their growth dynamics. In this issue, Rajappa and colleagues leverage a novel immunocompetent RCAS-BRAF V600E murine glioma model to profile the immunological dynamics taking place in BRAF V600E pLGG.

Sexually dimorphic computational histopathological signatures prognostic of overall survival in high-grade gliomas via deep learning.

High-grade glioma (HGG) is an aggressive brain tumor. Sex is an important factor that differentially affects survival outcomes in HGG. We used an end-to-end deep learning approach on hematoxylin and eosin (H&E) scans to (i) identify sex-specific histopathological attributes of the tumor microenvironment (TME), and (ii) create sex-specific risk profiles to prognosticate overall survival.

Dose Determination and Administration of Bacterial Extracellular Vesicles for In Vivo Preclinical Studies.

Essentially all bacteria secrete nano-sized (~20-200 nm) bacterial extracellular vesicles (bEVs) loaded with proteins, lipids, glycans, and nucleic acids. bEVs facilitate interactions among cells of the same species, different microbial species, and even with cells of multicellular organisms in the context of colonization or infection. Their interactions with host organism immune cell receptors vary depending on the producing bacterial species and are now being harnessed for the development of bEVs as a potential immunotherapeutic platform.

γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner.

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females.

Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer.

Background: Platinum resistance is the primary cause of poor survival in ovarian cancer (OC) patients. Targeted therapies and biomarkers of chemoresistance are critical for the treatment of OC patients. Our previous studies identified cell surface CD55, a member of the complement regulatory proteins, drives chemoresistance and maintenance of cancer stem cells (CSCs).

Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis.

Hematopoietic stem cells (HSCs) adapt to organismal blood production needs by balancing self-renewal and differentiation, adjusting to physiological demands and external stimuli. Although sex differences have been implicated in differential hematopoietic function in males versus females, the mediators responsible for these effects require further study. Here, we characterized hematopoiesis at a steady state and during regeneration following hematopoietic stem cell transplantation (HST).

MGMT Methylation and Differential Survival Impact by Sex in Glioblastoma.

: Sex differences in glioblastoma (GBM) have been observed in incidence, genetic and epigenetic alterations, and immune response. These differences have extended to the methylation of the MGMT promoter, which critically impacts temozolomide resistance. However, the association between sex, MGMT methylation, and survival is poorly understood, which this study sought to evaluate.