bims-cabrim 2022-10-09 papers

Front Cell Dev Biol. 2022 ;10 981583

Neuropilin-1 modulates the 3D invasive properties of glioblastoma stem-like cells.

Mathilde Kerhervé, Sara Rosińska, Kilian Trillet, Alya Zeinaty, Magalie Feyeux, Steven Nedellec, Julie Gavard.

Glioblastoma multiforme (GBM) is a rare, yet devastating, primary brain tumor in adults. Current treatments remain generally ineffective and GBM almost invariably recurs, resulting in median survival of 15 months. This high malignancy sources notably from the resilience and invasive capabilities of tumor cells. Within GBM, exists a population of self-sustaining transformed cells with stem-like properties (GSCs), which are thought to be responsible for tumor initiation, growth, and invasion, as well as recurrence. In the tumor microenvironment, GSCs might be found in the vicinity of brain endothelial cells, which provide a protective habitat. Likewise, these resistant, quiescent GSCs may accumulate in hypoxic zones, away from the perivascular niche, or travel towards the healthy brain parenchyma, by eminently co-opting neuro-vascular tracks. Herein, we established an ex vivo model to explore GSC invasive behavior. We found that patient-derived cells massively invade the collagen matrix. In addition, we described that the glycoprotein Neuropilin-1 (NRP1) contributes to GSC spreading and invasion. Indeed, both RNA interference-mediated silencing and CRISPR-mediated gene editing deletion of NRP1 strongly impaired the 3D invasive properties of patient-derived GSCs and their close localization to the brain blood vessels. Of note, other typical features of GSCs, such as expansion and self-renewal were maintained. From a mechanistic standpoint, this biological effect might rely on the expression of the β3 subunit integrin cell-extracellular matrix adhesive receptor. Our data, therefore, propose a reliable approach to explore invasive properties of patient glioma cells ex vivo and identify NRP1 as a mediator in this malignant process.

Keywords: adhesion; collagen; glioma; integrin; invasion; migration

DOI: https://doi.org/10.3389/fcell.2022.981583

Oncogene. 2022 Oct 01.

Neurotransmitter signaling: a new frontier in colorectal cancer biology and treatment.

Francesca Battaglin, Priya Jayachandran, Carly Strelez, Annika Lenz, Sandra Algaze, Shivani Soni, Jae Ho Lo, Yan Yang, Joshua Millstein, Wu Zhang, Evanthia T Roussos Torres, Jean C Shih, Shannon M Mumenthaler, Josh Neman, Heinz-Josef Lenz.

The brain-gut axis, a bidirectional network between the central and enteric nervous system, plays a critical role in modulating the gastrointestinal tract function and homeostasis. Recently, increasing evidence suggests that neuronal signaling molecules can promote gastrointestinal cancers, however, the mechanisms remain unclear. Aberrant expression of neurotransmitter signaling genes in colorectal cancer supports the role of neurotransmitters to stimulate tumor growth and metastatic spread by promoting cell proliferation, migration, invasion, and angiogenesis. In addition, neurotransmitters can interact with immune and endothelial cells in the tumor microenvironment to promote inflammation and tumor progression. As such, pharmacological targeting of neurotransmitter signaling represent a promising novel anticancer approach. Here, we present an overview of the current evidence supporting the role of neurotransmitters in colorectal cancer biology and treatment.

DOI: https://doi.org/10.1038/s41388-022-02479-4

Brain. 2022 Oct 03. pii: awac360. [Epub ahead of print]

Structural connectome quantifies tumour invasion and predicts survival in glioblastoma patients.

Yiran Wei, Chao Li, Zaixu Cui, Roxanne Claudeve Mayrand, Jingjing Zou, Adrianna Leanne Kok Chi Wong, Rohitashwa Sinha, Tomasz Matys, Carola Bibiane Schönlieb, Stephen John Price.

Glioblastoma is characterised by diffuse infiltration into the surrounding tissue along white matter tracts. Identifying the invisible tumour invasion beyond focal lesion promises more effective treatment, which remains a significant challenge. It is increasingly accepted that glioblastoma could widely affect brain structure and function, and further lead to reorganisation of neural connectivity. Quantifying neural connectivity in glioblastoma may provide a valuable tool for identifying tumour invasion. Here we propose an approach to systematically identify tumour invasion by quantifying the structural connectome in glioblastoma patients. We first recruit two independent prospective glioblastoma cohorts: Discovery cohort with 117 patients and Validation cohort with 42 patients. Next, we employ diffusion MRI of healthy subjects to construct tractography templates indicating white matter connection pathways between brain regions. Next, we construct fractional anisotropy skeletons from diffusion MRI using an improved voxel projection approach based on the tract-based spatial statistics, where the strengths of white matter connection and brain regions are estimated. To quantify the disrupted connectome, we calculate the deviation of the connectome strengths of patients from that of the age-matched healthy controls. We then categorise the disruption into regional disruptions based on the relative location of connectome to focal lesions. We also characterise the topological properties of the patient connectome based on the graph theory. Finally, we investigate the clinical, cognitive and prognostic significance of connectome metrics using Pearson correlation test, mediation test and survival models. Our results show that the connectome disruptions in glioblastoma patients are widespread in the normal-appearing brain beyond focal lesions, associated with lower pre-operative performance (P < 0.001), impaired cognitive function (P < 0.001), and worse survival (overall survival: hazard ratio = 1.46, P = 0.049; progression-free survival: hazard ratio = 1.49, P = 0.019). Additionally, these distant disruptions mediate the effect on topological alterations of the connectome (mediation effect: clustering coefficient: -0.017, P < 0.001, characteristic path length: 0.17, P = 0.008). Further, the preserved connectome in the normal-appearing brain demonstrates evidence of connectivity reorganisation, where the increased neural connectivity is associated with better overall survival (log-rank P = 0.005). In conclusion, our connectome approach could reveal and quantify the glioblastoma invasion distant from the focal lesion and invisible on the conventional MRI. The structural disruptions in the normal-appearing brain were associated with the topological alteration of the brain and could indicate treatment target. Our approach promises to aid more accurate patient stratification and more precise treatment planning.

Keywords: brain connectome; brain reorganisation; glioblastoma; survival analysis; tumour invasion

DOI: https://doi.org/10.1093/brain/awac360

Front Immunol. 2022 ;13 958620

From protein-protein interactions to immune modulation: Therapeutic prospects of targeting Neuropilin-1 in high-grade glioma.

Gregory T Smith, Daniel P Radin, Stella E Tsirka.

In the past several years there has been a marked increase in our understanding of the pathophysiological hallmarks of glioblastoma development and progression, with specific respect to the contribution of the glioma tumor microenvironment to the rapid progression and treatment resistance of high-grade gliomas. Despite these strides, standard of care therapy still only targets rapidly dividing tumor cells in the glioma, and does little to curb the pro-tumorigenic functions of non-cancerous cells entrenched in the glioma microenvironment. This tumor promoting environment as well as the heterogeneity of high-grade gliomas contribute to the poor prognosis of this malignancy. The interaction of non-malignant cells in the microenvironment with the tumor cells accentuate phenotypes such as rapid proliferation or immunosuppression, so therapeutically modulating one target expressed on one cell type may be insufficient to restrain these rapidly developing neoplasias. With this in mind, identifying a target expressed on multiple cell types and understanding how it governs tumor-promoting functions in each cell type may have great utility in better managing this disease. Herein, we review the physiology and pathological effects of Neuropilin-1, a transmembrane co-receptor which mediates signal transduction pathways when associated with multiple other receptors. We discuss its effects on the properties of endothelial cells and on immune cell types within gliomas including glioma-associated macrophages, microglia, cytotoxic T cells and T regulatory cells. We also consider its effects when elaborated on the surface of tumor cells with respect to proliferation, stemness and treatment resistance, and review attempts to target Neuroplin-1 in the clinical setting.

Keywords: Neuropilin-1 (NRP1); Treg cells; angiogenesis; cytotoxic T cell; glioma; glioma-associated macrophages and microglia; high grade glioma (HGG); hypoxia

DOI: https://doi.org/10.3389/fimmu.2022.958620

Neurotrauma Rep. 2022 ;3(1): 415-420

Cell-Free Mitochondrial DNA in Acute Brain Injury.

Saeed Kayhanian, Angelos Glynos, Richard Mair, Andras Lakatos, Peter J A Hutchinson, Adel E Helmy, Patrick F Chinnery.

Traumatic brain injury and aneurysmal subarachnoid haemorrhage are a major cause of morbidity and mortality worldwide. Treatment options remain limited and are hampered by our understanding of the cellular and molecular mechanisms, including the inflammatory response observed in the brain. Mitochondrial DNA (mtDNA) has been shown to activate an innate inflammatory response by acting as a damage-associated molecular pattern (DAMP). Here, we show raised circulating cell-free (ccf) mtDNA levels in both cerebrospinal fluid (CSF) and serum within 48 h of brain injury. CSF ccf-mtDNA levels correlated with clinical severity and the interleukin-6 cytokine response. These findings support the use of ccf-mtDNA as a biomarker after acute brain injury linked to the inflammatory disease mechanism.

Keywords: DAMP; acute brain injury; brain inflammation; mitochondrial DNA; subarachnoid hemorrhage; traumatic brain injury

DOI: https://doi.org/10.1089/neur.2022.0032

iScience. 2022 Oct 21. 25(10): 105124

Clinical neuroscience and neurotechnology: An amazing symbiosis.

Andrea Cometa, Antonio Falasconi, Marco Biasizzo, Jacopo Carpaneto, Andreas Horn, Alberto Mazzoni, Silvestro Micera.

In the last decades, clinical neuroscience found a novel ally in neurotechnologies, devices able to record and stimulate electrical activity in the nervous system. These technologies improved the ability to diagnose and treat neural disorders. Neurotechnologies are concurrently enabling a deeper understanding of healthy and pathological dynamics of the nervous system through stimulation and recordings during brain implants. On the other hand, clinical neurosciences are not only driving neuroengineering toward the most relevant clinical issues, but are also shaping the neurotechnologies thanks to clinical advancements. For instance, understanding the etiology of a disease informs the location of a therapeutic stimulation, but also the way stimulation patterns should be designed to be more effective/naturalistic. Here, we describe cases of fruitful integration such as Deep Brain Stimulation and cortical interfaces to highlight how this symbiosis between clinical neuroscience and neurotechnology is closer to a novel integrated framework than to a simple interdisciplinary interaction.

Keywords: Bioelectronics; Clinical neuroscience

DOI: https://doi.org/10.1016/j.isci.2022.105124