A novel necroptosis-related gene index for predicting prognosis and a cold tumor immune microenvironment in stomach adenocarcinoma. Frontiers in immunology Background:Gastric cancer (GC) represents a major global clinical problem with very limited therapeutic options and poor prognosis. Necroptosis, a recently discovered inflammatory form of cell death, has been implicated in carcinogenesis and inducing necroptosis has also been considered as a therapeutic strategy. Objective:We aim to evaluate the role of this pathway in gastric cancer development, prognosis and immune aspects of its tumor microenvironment. Methods and results:In this study, we evaluated the gene expression of 55 necroptosis-related genes (NRGs) that were identified carrying out a comprehensive review of the medical literature. Necroptosis pathway was deregulated in gastric cancer samples (n=375) as compared to adjacent normal tissues (n=32) obtained from the "The Cancer Genome Atlas (TCGA)". Based on the expression of these NRGs, two molecular subtypes were obtained through consensus clustering that also showed significant prognostic difference. Differentially expressed genes between these two clusters were retrieved and subjected to prognostic evaluation univariate cox regression analysis and LASSO cox regression analysis. A 13-gene risk signature, termed as necroptosis-related genes prognostic index (NRGPI), was constructed that comprehensively differentiated the gastric cancer patients into high- and low-risk subgroups. The prognostic significance of NRGPI was validated in the GEO cohort (GSE84437: n=408). The NRGPI-high subgroup was characterized by upregulation of 10 genes (CYTL1, PLCL1, CGB5, CNTN1, GRP, APOD, CST6, GPX3, FCN1, SERPINE1) and downregulation of 3 genes (EFNA3, E2F2, SOX14). Further dissection of these two risk groups by differential gene expression analysis indicated involvement of signaling pathways associated with cancer cell progression and immune suppression such as WNT and TGF-β signaling pathway. Para-inflammation and type-II interferon pathways were activated in NRGPI-high patients with an increased infiltration of Tregs and M2 macrophage indicating an exhausted immune phenotype of the tumor microenvironment. These molecular characteristics were mainly driven by the eight NRGPI oncogenes (CYTL1, PLCL1, CNTN1, GRP, APOD, GPX3, FCN1, SERPINE1) as validated in the gastric cancer cell lines and clinical samples. NRGPI-high patients showed sensitivity to a number of targeted agents, in particular, the tyrosine kinase inhibitors. Conclusions:Necroptosis appears to play a critical role in the development of gastric cancer, prognosis and shaping of its tumor immune microenvironment. NRGPI can be used as a promising prognostic biomarker to identify gastric cancer patients with a cold tumor immune microenvironment and poor prognosis who may response to selected molecular targeted therapy. 10.3389/fimmu.2022.968165

Recent advances in the developmental origin of neuroblastoma: an overview. Ponzoni Mirco,Bachetti Tiziana,Corrias Maria Valeria,Brignole Chiara,Pastorino Fabio,Calarco Enzo,Bensa Veronica,Giusto Elena,Ceccherini Isabella,Perri Patrizia Journal of experimental & clinical cancer research : CR Neuroblastoma (NB) is a pediatric tumor that originates from neural crest-derived cells undergoing a defective differentiation due to genomic and epigenetic impairments. Therefore, NB may arise at any final site reached by migrating neural crest cells (NCCs) and their progeny, preferentially in the adrenal medulla or in the para-spinal ganglia.NB shows a remarkable genetic heterogeneity including several chromosome/gene alterations and deregulated expression of key oncogenes that drive tumor initiation and promote disease progression.NB substantially contributes to childhood cancer mortality, with a survival rate of only 40% for high-risk patients suffering chemo-resistant relapse. Hence, NB remains a challenge in pediatric oncology and the need of designing new therapies targeted to specific genetic/epigenetic alterations become imperative to improve the outcome of high-risk NB patients with refractory disease or chemo-resistant relapse.In this review, we give a broad overview of the latest advances that have unraveled the developmental origin of NB and its complex epigenetic landscape.Single-cell RNA sequencing with spatial transcriptomics and lineage tracing have identified the NCC progeny involved in normal development and in NB oncogenesis, revealing that adrenal NB cells transcriptionally resemble immature neuroblasts or their closest progenitors. The comparison of adrenal NB cells from patients classified into risk subgroups with normal sympatho-adrenal cells has highlighted that tumor phenotype severity correlates with neuroblast differentiation grade.Transcriptional profiling of NB tumors has identified two cell identities that represent divergent differentiation states, i.e. undifferentiated mesenchymal (MES) and committed adrenergic (ADRN), able to interconvert by epigenetic reprogramming and to confer intra-tumoral heterogeneity and high plasticity to NB.Chromatin immunoprecipitation sequencing has disclosed the existence of two super-enhancers and their associated transcription factor networks underlying MES and ADRN identities and controlling NB gene expression programs.The discovery of NB-specific regulatory circuitries driving oncogenic transformation and maintaining the malignant state opens new perspectives on the design of innovative therapies targeted to the genetic and epigenetic determinants of NB. Remodeling the disrupted regulatory networks from a dysregulated expression, which blocks differentiation and enhances proliferation, toward a controlled expression that prompts the most differentiated state may represent a promising therapeutic strategy for NB. 10.1186/s13046-022-02281-w

Development of A novel ferroptosis-related prognostic signature with multiple significance in paediatric neuroblastoma. Frontiers in pediatrics Background:Ferroptosis is an iron-dependent regulated cell death pathway that plays an essential role in the occurrence and development of tumours. Nonetheless, little is known about the impact of ferroptosis-related genes (FRGs) on neuroblastoma. Methods:Transcriptional profiles and clinicopathological data of neuroblastoma were downloaded from the TARGET and GEO datasets. These were used as the training set and the validation set, respectively. Non-negative matrix factorisation was employed to divide patients with neuroblastoma into distinct ferroptosis clusters. The Cox regression model with LASSO was performed based on the FRGs to construct a multigene signature, which was subsequently evaluated in the testing set. Finally, we analysed the differences in the tumour immune microenvironment (TIME) and immunotherapeutic response among the different risk groups. Results:The two distinct ferroptosis subtypes were determined and correlated with different clinical outcomes and tumour-infiltrating immune cells (TIICs). A risk model was developed to explore the risk scores of the individual patients. Patients in the low-risk group survived significantly longer than those in the high-risk group and showed a good predictive performance in the testing set. The risk score was significantly linked to clinicopathological traits, and it was confirmed as an independent prognostic indicator for assessing the overall survival. We also found that patients with low-risk scores had a higher infiltration of TIICs and a better immunotherapeutic response. Conclusions:This study showed the potential role of FRGs in contributing to the clinical features, prognosis, TIME, and immunotherapy of neuroblastoma cases. Our findings offer a valuable basis for future research in targeting ferroptosis and its TIME and provide novel measures for the prevention and treatment of neuroblastoma. 10.3389/fped.2023.1067187

Comprehensive exploration of the involvement of cuproptosis in tumorigenesis and progression of neuroblastoma. BMC genomics BACKGROUND:Copper-induced cell death, or "cuproptosis," as an apoptotic process, has recently received much attention in human diseases. Recent studies on cuproptosis have provided novel insights into the pathogenesis of various diseases, especially cancers. However, the association between neuroblastoma (NB) and cuproptosis in terms of their clinical outcomes, tumorigenesis, and treatment response remains unclear. METHODS:To determine the role of cuproptosis in NB tumorigenesis and progression, this study employed a systematic technique to explore the characteristic patterns of 10 key cuproptosis-related genes (CUGs) in NB. Consensus clustering analysis of the TARGET and GEO databases divided the NB patients into two subgroups that showed different clinicopathological attributes, molecular patterns, survival outcomes, disease-associated pathways, tumor immune microenvironment (TIME) features, and treatment responses. Moreover, a cuproptosis scoring scheme was established, which divided the patients with NB into two groups with high scores and low scores as per the median score. Furthermore, this research developed a nomogram and risk signature on the basis of this cuproptosis score to better elucidate its function in predicting NB prognosis. In vitro experiments were carried out using Transwell Assay, HLECs tube formation assay, Colony formation assay, Western Blotting Assay, Immunohistochemical (IHC) Staining, Immunofluorescence (IF) Staining and Flow Cytometry Analysis. RESULTS:The results demonstrated that the established cuproptosis score and prediction model could effectively distinguish between the individuals in low and high-risk groups and had a high predictive value. Lastly, bioinformatics analysis and in vitro experiments enabled the identification of PDHA1, a key CUG, which was involved in both DNA replication-related pathways and the cell cycle. It was also associated with tumorigenesis and progression of NB. CONCLUSION:Cuproptosis, especially PDHA1, play a crucial role in the TIME characteristics, tumor progression, and long-term prognosis of NB. The patterns of cuproptosis assessed in this research may improve the understanding of the overall concept of NB tumorigenesis, thus facilitating the development of more effective therapeutic interventions. 10.1186/s12864-023-09699-2