Neuro-oncology advances最新文献

Abstract: BackgroundEmbryonal tumor with multilayered rosettes (ETMR) is an aggressive pediatric brain tumor that carries a poor prognosis, and there is currently no standard of care. Dysregulated mitochondrial bioenergetics and dynamics have been associated with the progression of diverse cancers. Cardiolipins are mitochondrial-specific lipids, and their fatty acid composition has been shown to regulate mitochondrial structure and function. Despite the known functional significance of cardiolipins, their structure-specific accumulation in relation to mitochondrial phenotypes in ETMR remains ill-defined.

Methods: Spatial lipidomic profiles in patient samples and 3D models were determined using mass spectrometry imaging. Cell proliferation and mitochondrial bioenergetics and dynamics were characterized using immunohistochemistry, transmission electron microscopy, Western blotting, and metabolic assays. LCLAT1 KD was carried out using siRNA.

Results: We detected a structure-specific accumulation of cardiolipins and increased expression of the cardiolipin acyl chain remodeling enzyme, lysocardiolipin acyltransferase 1 (LCLAT1), within proliferating tumor cells in patient samples and the 3D tumorspheres. Orthogonal imaging techniques correlated the structure-specific accumulation of cardiolipin with fragmented mitochondria displaying aberrant cristae structure, altered mitochondrial dynamics, decreased expression of respiratory chain enzymes, and a more glycolytic phenotype. LCLAT1 KD altered cardiolipin profiles, reduced growth and proliferation, decreased Sox2 and N-Myc expression, increased p53 and p21 expression, and increased LIN28A and Dcx expression. Additional therapeutic targeting of the fragmented mitochondrial phenotype identified also resulted in selective inhibition of ETMR growth and viability.

Conclusions: Our findings provide novel insight into ETMR biology based on mitochondrial phenotypes and the fatty acid composition of the multifunctional mitochondrial-specific lipid, cardiolipin.

Background: ¹¹C-methionine positron emission tomography is one of the most reliable imaging modalities for -glioblastoma visualization. This investigation aimed to generate an ¹¹C-methionine positron emission tomography-like image, "Gliomap," from contrast-enhanced magnetic resonance imaging via a conditional Generative Adversarial Network (Gliomap-GAN).

Methods: Eighty-one newly diagnosed glioblastoma patients with preoperative contrast-enhanced magnetic resonance imaging and ¹¹C-methionine positron emission tomography were retrospectively collected. T1-weighted, T2-weighted, and Gd-enhanced T1-weighted images were co-registered and intensity normalized, followed by the creation of a contrast-enhancement subtraction map. They were used as source data to train Gliomap-GAN, targeting the corresponding ¹¹C-methionine positron emission tomography image. The training dataset comprised 2459 images augmented to 4918 pairs by mirroring. The test dataset consisted of 593 pairs. Furthermore, an additional five patients with 16 image-guided sampled tissues were used for histological validation of the generated Gliomap.

Results: Gliomaps visually resembled the original ¹¹C-methionine positron emission tomography images. The residual error between Gliomaps and the original images from test datasets was 0.07 ± 0.04 (mean ± SD) in tumor-to-normal tissue ratio. The Sørensen-Dice coefficient between the lesions predicted by Gliomap and ¹¹C-methionine positron emission tomography reached 0.88 ± 0.07 (mean ± SD) at a threshold of tumor-to-normal tissue ratio of 1.5. The absolute values of Gliomap showed a significant positive correlation with tumor cell density (P = .02).

Conclusion: The present research demonstrates that the Gliomap, generated from contrast-enhanced magnetic resonance imaging using generative artificial intelligence, is a promising imaging surrogate for visualizing tumor cell density in newly diagnosed glioblastoma.

Background: Differentiating recurrent tumor from post-treatment changes remains a major challenge in glioblastoma (GBM) patients. In this work, we compared the performance of 2 different MR perfusion techniques, dynamic susceptibility contrast (DSC), and arterial spin labeling (ASL) to differentiate recurrent tumor and post-treatment changes from the volume of cellular tumor segmented from combined Deep Learning and multimodal MRI measurements, including multishell diffusion and perfusion.

Methods: In this retrospective study, 137 MRIs from 107 patients with GBM were analyzed. Cellular tumor maps were segmented by 2 radiologists based on imaging, clinical history, and pathology. Multimodal MRI with perfusion and multishell diffusion were inputted into 5 nnU-Net Deep Learning models using either DSC or ASL with combination of multishell diffusion and standard MRI sequences to segment cellular tumor. Models with DSC and ASL were compared using segmentation performance (Dice score) and accuracy to detect recurrent tumor from post-treatment changes (area under the curve [AUC] under the receiver operating characteristic curve).

Results: Segmentation performances were similar in both cases, with a median Dice score of 0.75 (IQR: 0.53-0.84) for ASL and 0.76 (IQR: 0.57-0.84). AUC was 0.88 (CI 0.82-0.94) for ASL and 0.86 (CI, 0.80-0.92) for DSC, and this difference was statistically significant (P < .05, n = 10 000 permutation test). In 11 individual cases, recurring disease was detected with ASL but missed with cerebral blood volume, including recurring tumor in the vicinity of a surgical cavity (n = 5), close to the skull base (n = 1), and adjacent to an Ommaya reservoir (n = 2).

Conclusions: Our results demonstrate the utility of ASL in regions where susceptibility artifacts decrease the quality of DSC images.

Background: Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options and high recurrence rates. The blood-brain barrier (BBB) impedes therapeutic delivery for the brain, limiting systemic treatment efficacy. Focused ultrasound (FUS) combined with microbubbles (MBs) can transiently open the BBB (BBBO), enhancing drug delivery and modulating the tumor immune microenvironment (TME). However, the disorganized and leaky vasculature in GBM limits the effectiveness of FUS-mediated BBBO. Vascular normalization using antiangiogenic therapy may enhance both immune modulation and delivery. This study aimed to investigate whether vascular normalization via VEGFR-2 blockade with DC101, alone or in combination with FUS+MBs, improves TME remodeling in a murine GBM model.

Methods: CT2A glioma-bearing mice were treated with DC101, a VEGFR2 inhibitor, either alone or in combination with FUS+MBs. Tumor growth, survival, vessel permeability, immune cell profiling, and adhesion molecule expression were evaluated using immunohistochemistry, flow cytometry, and confocal microscopy.

Results: DC101 monotherapy significantly reduced tumor growth and prolonged survival. It reduced tumor vessel permeability and increased ICAM1 expression on CD31⁺ endothelial cells, consistent with vascular normalization. DC101 also reduced FOXP3⁺ regulatory T cells (Tregs) and increased the CD8/Treg ratio, indicating a more immunostimulatory TME. However, the addition of FUS+MBs in this normalized vascular environment did not further alter the immune landscape, suggesting a stable, quiescent TME.

Conclusion: DC101-mediated vascular normalization beneficially remodels the GBM TME and creates a quiescent platform for supporting future FUS-based therapeutic delivery. This combinatorial strategy offers a promising approach to overcoming BBB-related barriers in glioma treatment.

Background: GBM disproportionately affects older adults, who experience worse survival outcomes and reduced tolerance to aggressive therapies. Despite this, most preclinical GBM studies rely on young animal models, limiting insight into how aging influences tumor progression and treatment vulnerability. The aim of this study was to determine how aging alters glioma growth, survival outcomes, and host brain responses.

Methods: We used a syngeneic murine glioma model to compare young (6-7 weeks) and aged (85-86 weeks) mice implanted with SB28 glioma cells. We assessed survival, functional status (nesting behavior, weight loss), whole-brain tumor infiltration, and glial reactivity. Quantitative histology and image registration to the Allen Brain Atlas enabled region-specific tumor and glial burden analyses.

Results: Aged glioma-bearing mice exhibited significantly reduced survival, increased functional impairment (including impaired nesting and weight loss), and broader tumor infiltration, particularly within white matter tracts. Tumor volume alone did not account for these differences; multivariable logistic regression identified age as the only independent predictor of mortality. Aged brains also displayed heightened extratumoral neuroinflammation, especially in regions involved in motivation and cognitive function.

Conclusions: Aging is associated with a brain environment that permits greater glioma infiltration and is further characterized by heightened glial reactivity and reduced functional resilience to tumor burden. These findings underscore the limitations of relying solely on young animal models in GBM research and support incorporating aging as a critical variable. Targeting neuroinflammatory responses in the aged brain may represent a promising adjunct strategy to improve survival and preserve neurological function in older GBM patients.

Abstract: BackgroundGIntratumoral and intertumoral heterogeneity combined with immunosuppressive tumor microenvironments (TME) contribute to the poor outcomes associated with glioblastoma (GBM). Well-characterized immunocompetent models that recapitulate human GBM features are urgently needed to identify targets in the TME and develop novel therapeutics. Here, we used multiomic approaches to characterize syngeneic mouse brain tumor stem cell lines in vitro and in orthotopically engrafted tumors.

Methods: Whole-genome sequencing, transcriptomics, ATAC-sequencing, and imaging mass cytometry were used to characterize syngeneic brain tumor stem cell lines derived from Trp53^+/-/Nf1^+/- C57Bl6 mice. Mouse and human bulk, single-cell, and spatial sequencing datasets were analyzed for validation. CRISPR/Cas9 and shRNA were used for gene knockdowns. Tumor growth was investigated using orthotopic engraftment in syngeneic C57Bl6 mice.

Results: One of the syngeneic lines, mBT0309, generated tumors with histopathological characteristics of GBM. mBT0309 displayed amplification and high expression of Igf2. Copy number gains at the IGF2 locus were observed in human GBM tumors and stem cell lines. Furthermore, we determined that high IGF2 RNA expression is associated with poor survival in GBM patients. Imaging mass cytometry on mBT0309 tumors showed early infiltration of monocyte-derived macrophages, vascularization, and cell states characteristic of human GBM. Genetic targeting of Igf2 decreased in vitro cell growth, improved survival of engrafted mice, and decreased the percentage of Arginase-1+ macrophages in mBT0309 tumors.

Conclusions: mBT0309 is a valuable syngeneic model for studying immunosuppression and therapeutic resistance in GBM. IGF2 offers promise as a valuable therapeutic target to combat tumor growth and immunosuppression in GBM patients.

Background: Although schwannomas are common and benign, their growth patterns are often hard to predict. Currently, surgery and radiotherapy are the only standard treatments. Since metabolites are the end products of genes and proteins, metabolomics may reveal downstream tumor features in ways that other -omics cannot. Here, we use metabolomic profiling and stable isotope tracing to characterize primary human schwannomas and describe their changes following radiation in patient-derived xenografts.

Methods: Schwannomas collected during surgical resection underwent metabolomic profiling with gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry (N = 44) as well as DNA methylation profiling (N = 29). Large tumors were also implanted subcutaneously in athymic mice as patient-derived xenografts. Mice were randomized to radiation treatment or control 4-6 weeks post-implantation. Xenografts were harvested 72 h after radiation for metabolomic profiling (N = 53). Another group of xenografts (N = 33) was injected with U-¹³C-glutamine prior to tumor harvest for stable isotope tracing.

Results: The schwannoma metabolome differs from that of Schwann cells, and metabolomics-based clustering of schwannomas resembles DNA methylation-based classification. In xenografts, radiation decreases cellular proliferation and produces small but detectable changes to the tricarboxylic acid (TCA) cycle and nucleotide metabolism. ¹³C-glutamine tracing shows that schwannomas can produce urea cycle intermediates, TCA cycle intermediates, cytosine monophosphate (CMP), and cytosine triphosphate from glutamine even after radiation. CMP was the only metabolite with altered ¹³C uptake following radiation.

Conclusions: Schwannomas have distinct metabolic signatures compared to the Schwann cells from which they originate. Schwannoma xenograft metabolism is surprisingly robust to radiotherapy, and xenografts readily incorporate glutamine into the TCA cycle, urea cycle, and pyrimidine synthesis.

Background: Cerebrospinal fluid cell-free DNA (cfDNA) can detect and monitor leptomeningeal disease but has not been previously used to monitor parenchymal lesions.

Methods: Herein, we report our initial experience with CSF cfDNA monitoring for 2 patients with colorectal cancer (CRC) metastases to the thalamus, causing obstructive hydrocephalus.

Results: CSF samples were obtained during ventriculoperitoneal shunt placement, demonstrating high levels of cfDNA in both cases. Several genomic alterations detected in the cfDNA sequencing matched those in the tumor tissue biopsy. Follow-up CSF evaluations after subsequent therapy were used to help adjudicate pseudo-progression versus true progression.

Conclusions: Neither patient developed leptomeningeal disease, demonstrating CSF's utility in evaluating solitary brain metastases in direct contact with a CSF compartment.

While many postmitotic cells in the body harbor cilia, certain aggressive cancers such as glioblastoma (GBM) display low frequencies of cells harboring a primary cilium. Ciliated GBM cells that plan to multiply have to disassemble their cilium in order for centrioles to duplicate and re-purpose for mitosis. Little is known about the molecular mechanisms underlying cilia disassembly in GBM, or whether this may represent a driving factor in disease onset, progression, or recurrence. In many cell types, ciliary disassembly is thought to be orchestrated by the aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) signaling axis. These molecules are often overexpressed in GBM, perhaps owing to the less frequent observation of ciliated GBM cells. Here, we review regulators of the core pathway, and discuss recent studies attempting to inhibit AURKA and HDAC6 in patient and mouse models of GBM and resulting effects on cilia. In the face of potent inhibitors, GBM cells appear to engage pathways independent of the core axis to promote cilia disassembly and/or engage other forms of modified axonemal tubulin to ensure persistence of cilia on GBM cells. GBMs upregulate a host of proteins implicated to drive cilia disassembly. Thus, clarifying these alternate mechanisms may be important as the roles of cilia in tumor formation and propagation, angiogenesis, and treatment resistance are increasingly reported. A deeper understanding of the role of cilia in these hallmarks of glioma may hold clues to the high recurrence rate of GBM.

Background: Specific herpesviruses have been implicated in glioma development. We undertook a pilot study to examine whether herpesviruses-specific human T-cell receptor (TCR) sequences in patient blood samples associate with glioma grade and survival.

Methods: The study was based on 56 pretreatment blood samples collected from both patients with glioblastoma (n = 36) with varying survival times as well as 20 lower grade glioma patients, including astrocytomas and oligodendrogliomas. Following PCR amplification and high-throughput sequencing of DNA extracted from peripheral blood, data were analyzed (AdaptiveBiotechnologies ImmunoSEQ Analyzer) to identify complementarity-determining (CDR3) regions of human TCRs specific to herpes viral antigens. We identified sequences specific for six cytomegalovirus (CMV) peptides and ten Epstein-Barr virus peptides. No CDR3 sequences specific for Varicella Zoster could be identified in the publicly available databases queried.

Results: Blood samples yielded large numbers of productive rearrangements (ie CDR3 sequences resulting in functional T-cell immunity), and one or more sequences targeting CMV and EBV were found in every patient sample. For both EBV and CMV, we observed a greater breadth (higher average number of unique CDR3 sequences) and intensity (higher average sum of all CDR3 sequences) of antiviral T-cell response in patients with lower-grade gliomas compared with glioblastoma, even after adjustment for patient age and sex in multivariate regression models.

Conclusions: Interrogation of blood samples for CDR3 sequences describing the human TCR repertoire offers a novel tool for investigating anti-viral immune response in glioma. More robust immunity to herpesviruses could result in cross-reactive, primed cyto-toxic immune responses that potentially suppress development of more aggressive tumors.