Histotripsy-initiated immune response in a neuroblastoma murine model
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319944 | GEO | 2026/02/18
REPOSITORIES: GEO
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Project description:The bone marrow (BM) is the third most frequent site of metastasis for solid tumors, creating an unfavorable clinical outcome. It provides a unique microenvironment that promotes growth of tumors, however, the role of different BM cells, their molecular features, and their interactions with tumor cells, are poorly defined. Here, we investigate the BM niche in neuroblastoma (NB), a pediatric cancer of the sympathetic nervous system. NB has been molecularly defined at the primary cancer site, yet, the metastatic site is poorly characterized. We performed single-cell transcriptomics (scRNA-seq) and epigenomic profiling (scATAC-seq) of BM aspirates from 11 subjects spanning three major NB subtypes: patients with MYCN amplification (MNA), ATRX mutations (ATRXmut), and cases that lack these alterations (sporadic): NB cases were then compared to five age-matched and metastasis-free BM (controls), followed by in-depth single cell analyses of tissue diversity and cell-cell interactions. We present the first map of the epigenetic and transcriptomic effects of bone marrow metastases. Our analyses demonstrate that tumor cells in the metastatic niche display plasticity that differs among NB subtypes. NB cells via cell-cell interaction signal to the bone marrow microenvironment, rewiring specifically monocytes, which exhibit M1 and M2 features, marked by activation of pro- and anti-inflammatory programs, and express tumor-promoting factors, reminiscent of tumor-associated macrophages. Our study may provide the basis for a therapeutic approach, targeting tumor-to-microenvironment interactions.
2023-07-20 | PXD036979 | Pride
Project description:High risk - neuroblastoma (HR-NB) is a pediatric solid tumor with high lethality. Half of HR-NB are driven by MYCN gene amplification (MNA). These HR-NBs require high dosage chemotherapy and often relapse. Moreover, current therapies can cause severe long-term side effects and new therapies are urgently needed. This study investigates a novel therapeutic approach targeting the metabolic vulnerabilities of MNA NB cells. We discovered that Diphenyleneiodonium chloride (DPI), an inhibitor 2 of flavoprotein enzymes and mitochondrial complex I, synergizes with mitoquinone mesylate (MitoQ), a mitochondria-targeted antioxidant in 2D and 3D in vitro models of NB. Similarly to DPI, MitoQ appears to have a greater effect on cells with higher MYCN levels. Furthermore, low nanomolar concentrations of MitoQ significantly decrease MYCN protein expression and induce differentiation of MNA cells. The DPI and MitoQ combination further synergizes with vincristine, a chemotherapeutic agent used in NB treatment. Phosphoproteomics and proteomics analysis suggests that the drug combination induces MNA NB cell death by arresting the cell cycle and inhibiting oxidative phosphorylation (OXPHOS) in the mitochondria. Thus, interference with mitochondrial metabolism may represent an effective strategy to enhance the activity of chemotherapeutic drugs in MNA-NB.
2025-10-20 | PXD069621 | Pride
Project description:Half of the patients with high-risk neuroblastoma (NB) who receive GD2-targeted monoclonal antibody do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to interleukin (IL)2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (ICs) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 to hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against NB. We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high NB cell lines in vitro. T-cell deficient mice with orthotopic patient-derived xenografts (PDXs) and immunocompetent mice with transplantable orthotopic NB were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq). Hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic NB, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing NB.
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Project description:The development of targeted therapies has provided new hope for an increasing number of cancer patients affected by previously incurable diseases. The clinical success of this approach, however, is limited by numerous challenges, including a better control of cell plasticity, particularly in refractory and metastatic patients. Here we addressed this question in Neuroblastoma (NB), an aggressive pediatric malignancy, which remains a clinical challenge for high-risk patients. NB originates from neural crest-derived progenitors through defective differentiation programs combined with oncogenic activity due to genetic and epigenetic alterations. In order to identify critical genes responsible for tumor aggressiveness we performed combined chromatin and transcriptome analyses on matched primary xenografts, spheroids and differentiated adherent cultures, which we derived from metastatic non-MYCN amplified (nMNA) NB patients. Our approach identified the kinase BMX among the most differentially regulated genes between patient-derived xenografts and spheroids versus adherent models. We further found that BMX expression is associated with high tumor stage and poor patient survival in multiple NB transcriptomic datasets and critical to maintain the self-renewal and tumorigenic potential of NB spheroids. Moreover, we uncovered a positive correlation between BMX expression and the mesenchymal tumor cell phenotype, which was previously associated with increased chemo-resistance. Finally, we show that BMX inhibitors can readily reverse this cellular state, increase the sensitivity of NB spheroids toward standard of care chemotherapy, and reduce tumor growth in preclinical NB models. Altogether, our study identifies BMX as a novel promising therapeutic target for high-risk patients with relapsed or refractory nMNA NB tumors.
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Project description:A distinctive feature of neuroblastoma (NB) tumors is their ability to secrete neuroendocrine mediators such as catecholamines, which through β-adrenergic receptors ligation may influence different signaling pathways in the tumor microenvironment (TME). Here, we aimed to investigate whether the β3-AR modulation affected the host immune system response to NB tumor. In a murine syngeneic NB model, pharmacological β3-AR antagonism lead to an immune response reactivation and reduced tumor growth through the involvement of PD-1/PD-L1 signaling axis. Indeed, β3-AR blockade on tumor infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ and reduced PD-L1 expression on NB tumor cells, preventing the establishment of an immune suppressive TME. Furthermore, genomic analysis on NB patients showed that high ADRB3 gene expression correlates with poor clinical outcome. Overall, these findings indicate that β3-AR is able to sustain an immune suppressive TME in NB via PD-1/PD-L1 crosstalk, and suggest that targeting β-adrenergic signaling in NB could represent a new strategy to overcome immune escape gateway.
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Project description:Neuroblastoma (NB) is the most common extracranial malignant tumor in children. Although the survival rate of NB has improved over the years, the outcome of NB still remains poor for over 30% of cases. A more accurate risk stratification remains a key point in the study of NB and the availability of novel prognostic biomarkers of 'high-risk' at diagnosis could help improving patient stratification and predicting outcome. In this paper we show a biomarker discovery approach applied to the plasma of 172 NB patients. Plasma samples from a first cohort of NB patients and age-matched healthy controls were used for untargeted metabolomics analysis based on high-resolution mass spectrometry (HRMS). Differential expression analysis highlighted a number of metabolites annotated with a high degree of identification. Among them, 3-O-methyldopa (3-O-MD) was validated in a second cohort of NB patients using a targeted metabolite profiling approach and its prognostic potential was also analyzed by survival analysis on patients with 3 years follow-up. High expression of 3-O-MD was associated with worse prognosis in the subset of patients with stage M tumor (log-rank p < 0.05) and, among them, it was confirmed as a prognostic factor able to stratify high-risk patients older than 18 months. 3-O-MD might be thus considered as a novel prognostic biomarker of NB eligible to be included at diagnosis among catecholamine metabolite panels in prospective clinical studies. Further studies are warranted to exploit other potential biomarkers highlighted using our approach.
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Project description:A minimally parameterized mathematical model for low-dose metronomic
chemotherapy is formulated that takes into account angiogenic signaling between
the tumor and its vasculature and tumor inhibiting effects of tumor-immune system
interactions. The dynamical equations combine a model for tumor development under
angiogenic signaling formulated by Hahnfeldt et al. with a model for tumor-immune
system interactions by Stepanova. The dynamical properties of the model are analyzed.
Depending on the parameter values, the system encompasses a variety of medically
realistic scenarios that range from cases when (i) low-dose metronomic chemotherapy
is able to eradicate the tumor (all trajectories converge to a tumor-free equilibrium
point) to situations when (ii) tumor dormancy is induced (a unique, globally asymp-
totically stable benign equilibrium point exists) to (iii) multi-stable situations that have
both persistent benign and malignant behaviors separated by the stable manifold of
an unstable equilibrium point and finally to (iv) situations when tumor growth can-
not be overcome by low-dose metronomic chemotherapy. The model forms a basis
for a more general study of chemotherapy when the main components of a tumor’s
microenvironment are taken into account
2020-02-03 | MODEL2002030001 | BioModels