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Artificial-intelligence- and multi-omics-guided predictive and drug repurposing framework construction for colorectal cancer: evidence from succinylation-neutrophil signatures.
BACKGROUND: Succinylation-linked metabolic rewiring and neutrophil-driven inflammation are key drivers of colorectal carcinoma (COAD) progression; however, they have rarely been translated to an end-to-end artificial intelligence (AI) drug-design pipeline connecting target nomination, resistance-relevant tumor microenvironment states, and candidate evaluation. METHODS: We integrated bulk transcriptomes from The Cancer Genome Atlas colon adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus databases to derive succinylation-neutrophil (SN)-associated genes using the limma package, single-sample gene-set enrichment analysis, weighted gene coexpression network analysis, and protein-protein interaction network analysis; we then constructed a cross-cohort prognostic system by screening and selecting the machine-learning combination of random survival forest and ridge regression as the optimal predictor. To enable precision stratification, we applied deep-learning self-organizing maps (SOMs) to define the SN-driven molecular subtypes and characterized their immune and pathway heterogeneities at both bulk and single-cell resolutions through AI-powered virtual perturbation analysis to interrogate the cell-state shifts. Importantly, we extended AI approaches in drug design beyond risk modeling to a target-to-candidate workflow by nominating a druggable SN hub gene. We also performed co-culture in vitro assays for identifying NOX4 molecular insights into neutrophil patterns and their associations with COAD progression. RESULTS: Our approach identifies SN biology as a clinically actionable axis in COAD, highlights NOX4 as a central SN-associated target with immune relevance, and prioritizes talazoparib as a repurposing candidate supported by integrated in silico evidence. CONCLUSION: The findings of this study provide a precision-oncology blueprint that couples AI stratification with therapeutic nomination and evaluation.
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Disturbed flow induces reprogramming of endothelial cells to immune-like and foam cells under hypercholesterolaemia during atherogenesis.
AIMS: Atherosclerosis occurs preferentially in the arteries exposed to disturbed flow (d-flow), while the stable flow (s-flow) regions are protected even under hypercholesterolaemic conditions. We recently showed that d-flow alone initiates flow-induced reprogramming of endothelial cells (FIRE), including the novel concept of partial endothelial-to-immune-cell-like transition (partial EndIT), but it was not validated using a genetic lineage-tracing model. In addition, the combined effect of d-flow and hypercholesterolaemia has not been tested. Here, we tested and validated the two-hit hypothesis that d-flow is an initial instigator of partial FIRE but requires hypercholesterolaemia to induce a full-blown FIRE and atherosclerotic plaque development. METHODS AND RESULTS: Mice were treated with AAV-PCSK9 and a Western diet to induce hypercholesterolaemia and/or partial carotid ligation (PCL) surgery to expose the left common carotid artery (LCA) to d-flow. Single-cell RNA sequencing (scRNA-seq) analysis was performed using single cells obtained from the LCAs and the control right common carotid arteries at 2 and 4 weeks post-PCL. Immunohistochemical staining was performed on EC-specific confetti mice at 4 weeks post-PCL and hypercholesterolaemia to validate endothelial reprogramming. Human aortic endothelial cells (HAECs) exposed to d-flow and hypercholesterolaemic conditions were used to validate FIRE. Atherosclerotic plaques developed by d-flow under hypercholesterolaemia, but not by d-flow or hypercholesterolaemia alone. The scRNA-seq results of 98 553 single cells from 95 mice revealed 25 cell clusters: 5 EC, 3 vascular smooth muscle cell (SMC), 5 macrophage (MΦ), and additional fibroblast, T cell, natural killer cell, dendritic cell, neutrophil, and B-cell clusters. Our scRNA-seq analysis results raised a hypothesis that d-flow under hypercholesterolaemia transitioned healthy ECs to full immune-like (EndIT) and, more surprisingly, foam-like cells (EndFT), in addition to inflammatory and mesenchymal cells (EndMT). Further, ECs with characteristics of foam cells shared remarkably similar transcriptomic profiles with foam cells derived from SMCs and MΦs. Lineage-tracing studies using immunohistochemical staining of canonical protein and lipid markers in the EC-specific confetti mice exposed to d-flow and hypercholesterolaemia demonstrated evidence supporting the novel FIRE hypothesis, including EndIT and EndFT. Moreover, reanalysis of the two publicly available human plaque scRNA-seq datasets and our immunostaining studies suggest that FIRE occurs in human atherosclerotic plaques. Additionally, HAECs exposed to d-flow, high cholesterol, and proinflammatory cytokines (identified in our scRNA-seq data) show the markers of EndIT and EndFT at the mRNA, protein, and functional levels. CONCLUSION: The scRNA-seq study raised a two-hit hypothesis for FIRE, including EndIT and EndFT, which was validated by the lineage-tracing and in vitro HAEC studies. D-flow induces partial reprogramming, including inflammation, EndMT, and partial EndIT. Under hypercholesterolaemia, d-flow fully reprogrammes arterial ECs, including the novel EndIT and EndFT, in addition to inflammation and EndMT, during atherogenesis. This single-cell atlas and FIRE programs provide a crucial roadmap for novel mechanistic understanding and therapeutics targeting flow-sensitive genes, proteins, and pathways of atherosclerosis.
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The role of SEC14L4 in esophageal squamous cell cancer: insights into clinical relevance and molecular pathways.
BACKGROUND: Esophageal squamous cell cancer (ESCC) is the most common type of esophageal cancer. This study aimed to elucidate the role of Saccharomyces cerevisiae-like 4 (SEC14L4) in ESCC. METHODS: To elucidate the role of SEC14L4 in ESCC, this study analyzed the clinical data, gene sequencing data, and other relevant data retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The methodology involved several analytical approaches, including nomogram model analysis, co-expression analysis, gene set enrichment and variation analysis, weighted correlation network analysis, drug susceptibility analysis, and single-cell analysis. These methods were employed to evaluate the significance of SEC14L4 in ESCC. The expression of SEC14L4 was evaluated via quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SEC14L4 expression (P<0.001) was significantly elevated in those with ESCC, especially in patients with locally advanced disease (P=0.005), and indicated a poor prognosis (P=0.045). Findings from the nomogram model analysis identified the contribution of clinical indicators to survival prediction with good efficacy. Subsequently, the single-nucleotide polymorphisms and co-expressed genes of SEC14L4 were identified. Furthermore, pathways associated with SEC14L4, including DNA metabolic process, transcription factor binding, apoptosis, and others, were examined. Notably, SEC14L4 expression was predominantly observed in monocytes. Drug sensitivity analysis indicated the association of SEC14L4 expression with sensitivity of ESCC to the common chemotherapy drugs AICAR, BMS.708163, GNF.2, Nutlin.3a, PD.0325901, and RDEA119. Verification of the high expression of SEC14L4 in KYSE520 and KYSE150 was conducted, thereby confirming the study's findings. CONCLUSIONS: High expression of SEC14L4 is associated with poorer clinical outcomes, highlighting its potential as a therapeutic target and suggesting its involvement in the molecular mechanisms underlying ESCC.
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XBP1 impacts lung adenocarcinoma progression by promoting plasma cell adaptation to the tumor microenvironment.
Background: The activation of X-box binding protein 1 (XBP1) plays an essential role in the unfolded protein response (UPR) of the endoplasmic reticulum (ER). XBP1 is commonly expressed in various tumors and is closely related to tumorigenesis and progression. However, the role of XBP1 in lung adenocarcinoma (LUAD), especially the prognostic value of its alternative splicing isoforms, remains largely unknown. Methods: The LUAD datasets were retrieved from the The Cancer Genome Atlas, ArrayExpress and Gene Expression Omnibus. GEPIA2 and meta-analysis were employed to explore the prognostic value, and bioinformatics analysis with the TIMER2.0 database was used to investigate immune cell infiltration. We performed single-cell analyses to identify cell types with high XBP1 expression. In addition, polymerase chain reaction (PCR) and DNA sequencing were performed to verify the authenticity of the new spliceosome. Results: In this study, we found that high expression of XBP1 was significantly associated with a good prognosis, and XBP1 expression was significantly positively correlated with B cell infiltration in LUAD. In addition, we found that high-level expression of a novel splicing isoform, XBP1 (XBP1-003), improved the prognosis of LUAD. Protein structural analysis demonstrated that XBP1-003 has several specific protein domains that are different from those of other XBP1 isoforms, indicating a unique function of this isoform in LUAD. Conclusion: All these results suggest that XBP1 plays an antitumorigenic role in LUAD through alternative splicing, which may be related to the adaptation of plasma cells. This sheds new light on the potential strategy for LUAD prognosis evaluation and immunotherapy.
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Single-nucleus transcriptome profiling provides insights into the pathophysiology of OSA-related renal injury.
Obstructive sleep apnea (OSA) has been demonstrated to be associated with renal injury. However, the cellular and molecular mechanisms by which chronic intermittent hypoxia (CIH), a hallmark of OSA, contributes to renal injury remain poorly understood. Twelve male Sprague-Dawley rats were randomized into normoxic control (NC) and CIH groups (n = 6 each), with CIH exposure for 12 weeks. Renal injury was evaluated by Hematoxylin and Eosin staining and a modified Jablonski score. Single-nucleus RNA sequencing (snRNA-seq) was performed. Data analysis included clustering of cells, differential gene expression analysis, and functional enrichment through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Histopathological analysis revealed renal injury with renal tubular epithelial cell edema, necrosis in the CIH group compared to NC. A total of 42,581 cells (19,655 cells from NC group and 22,926 cells from CIH group) were retained after quality control, with 13 distinct renal cell populations identified. CIH exposure resulted in an increased proportion of podocytes, while mesangial cells were reduced compared to the NC group. CIH exposure altered the transcriptomic landscape, with differentially expressed genes (DEGs) observed across multiple cell types. Functional enrichment analysis indicated that CIH-induced DEGs were associated with suppressed metabolic and signaling pathways in proximal tubule and loop of Henle epithelial cells, activation of apoptotic and sodium reabsorption pathways in distal convoluted tubule cells, and enhanced inflammatory and phagocytic signaling in mononuclear phagocytes. Our study provides a high-resolution atlas of CIH-induced transcriptional changes in the rat kidney. The findings reveal cell type-specific responses and pathways potentially contributing to OSA-associated renal injury, offering novel insights into pathogenesis and potential therapeutic targets for preventing renal damage in OSA patients.
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Single-cell characterization of self-renewing primary trophoblast organoids as modeling of EVT differentiation and interactions with decidual natural killer cells.
BACKGROUND: Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are critical events for placentation. However, appropriate in vitro modelling system and regulatory programs of these two events are still lacking. Recent trophoblast organoid (TO) has advanced the molecular and mechanistic research in placentation. Here, we firstly generated the self-renewing TO from human placental villous and differentiated it into EVTs (EVT-TO) for investigating the differentiation events. We then co-cultured EVT-TO with freshly isolated decidual NKs for further study of cell communication. TO modelling of EVT differentiation as well as EVT interaction with dNK might cast new aspect for placentation research. RESULTS: Single-cell RNA sequencing (scRNA-seq) was applied for comprehensive characterization and molecular exploration of TOs modelling of EVT differentiation and interaction with dNKs. Multiple distinct trophoblast states and dNK subpopulations were identified, representing CTB, STB, EVT, dNK1/2/3 and dNKp. Lineage trajectory and Seurat mapping analysis identified the close resemblance of TO and EVT-TO with the human placenta characteristic. Transcription factors regulatory network analysis revealed the cell-type specific essential TFs for controlling EVT differentiation. CellphoneDB analysis predicted the ligand-receptor complexes in dNK-EVT-TO co-cultures, which relate to cytokines, immunomodulation and angiogenesis. EVT was known to affect the immune properties of dNK. Our study found out that on the other way around, dNKs could exert effects on EVT causing expression changes which are functionally important. CONCLUSION: Our study documented a single-cell atlas for TO and its applications on EVT differentiation and communications with dNKs, and thus provide methodology and novel research cues for future study of human placentation.
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Single-cell transcriptomics reveal oxidative phosphorylation and oxidative stress in the superior temporal plane of non-syndromic cleft lip and palate fetuses.
AIM: Non-syndromic cleft lip and palate (NSCLP) is a common congenital disability that causes morphological and functional abnormalities in the craniofacial region. Many studies have focused on clinical treatments and surgical aspects, but there has been limited investigation into the neural mechanisms in individuals with NSCLP. Therefore, it remains unclear whether developmental abnormalities in the brains of NSCLP fetuses exist. MATERIALS AND METHODS: To investigate the presence of developmental abnormalities in the brains of NSCLP fetuses, we performed single-nucleus RNA sequencing (snRNA-seq) on the superior temporal plane (STP) from three NSCLP fetuses and three normal fetuses. Samples were collected at 17-23 gestational weeks. Real-time quantitative PCR (RT-qPCR) and immunofluorescence were performed to validate further phenotypes identified in the sequencing data. KEY FINDINGS: Following dimensionality reduction and clustering, we identified seven distinct cell types. Cell abundance changes revealed that excitatory neurons, inhibitory neurons, and astrocytes varied dramatically. We further identified the abnormally increased levels of oxidative phosphorylation (OXPHOS) and oxidative stress in the STP of NSCLP fetuses. Further investigation determined that a specific subpopulation of inhibitory neurons, InN6, is closely associated with altered OXPHOS and oxidative stress, potentially contributing to abnormal brain development in NSCLP. Finally, immunofluorescence and RT-qPCR results confirmed the abnormal increase in OXPHOS and oxidative stress in the NSCLP fetuses' brain. SIGNIFICANCE: This study provides a single-cell atlas of STP in the NSCLP fetuses, revealing increased OXPHOS and oxidative stress in the NSCLP fetal brain. These findings provide new insights into the pathological mechanisms of the brain in NSCLP.
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Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma.
Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG frequently develops in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-sequencing, we identify ectopic expression of neuromuscular molecules in MG-type thymoma. These molecules are found within a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we name neuromuscular mTECs (nmTECs). MG-thymoma also exhibits microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicts the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma is further confirmed immunohistochemically and by cellular composition estimation from the MG-thymoma transcriptome. Altogether, this study suggests that nmTECs have a significant function in MG pathogenesis via ectopic expression of neuromuscular molecules.
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A Novel Cholesterol Metabolism-Related lncRNA Signature Predicts the Prognosis of Patients with Hepatocellular Carcinoma and Their Response to Immunotherapy.
BACKGROUND: The survival rate of hepatocellular carcinoma (HCC) is low and the prognosis is poor. Metabolic reprogramming is still an emerging hallmark of cancer, and reprogramming of cholesterol metabolism plays a crucial action in tumor pathogenesis. Increasing evidence suggests that cholesterol metabolism affects the cell proliferation, invasion, migration, and resistance to chemotherapy of HCC. To date, no long noncoding RNA (lncRNA) signature associated with cholesterol metabolism has been developed to predict the outcome of patients with HCC. METHODS: The RNA-seq data as well as the prognostic and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. We conducted univariate and multivariate analyses to assess cholesterol metabolism-related lncRNAs correlated with the prognosis of patients with HCC in order to construct a prognostic signature. Functional differences between low- and high-risk groups were investigated using genomic enrichment analysis (GSEA). Kaplan-Meier (KM) curves were applied to explore the overall survival (OS) of the low- and high-risk groups. Single-sample genomic enrichment analysis (ssGSEA) was applied to investigate the association between this predictive signature and immune function. We subsequently examined how this signature relates to treatment response in HCC patients. RESULTS: A prognostic signature comprising six lncRNAs related to cholesterol metabolism was constructed (AC124798.1, AL031985.3, AC103760.1, NRAV, WAC-AS1 and AC022613.1). We found that low-risk groups showed a better prognosis than high-risk groups. In HCC patients, the cholesterol metabolism-related lncRNA signature may be served as an independent prognostic factor. Cholesterol metabolism-related lncRNA signature had higher diagnostic efficiency compared to clinicopathologic variables. After stratifying patients according to different clinicopathological variables, patients with low-risk had a longer OS compared with high-risk patients. The ssGSEA demonstrated that this signature was closely related to the immune status of HCC patients. GSEA analysis demonstrated that immune- and tumor-related pathways were predominantly enriched in the high-risk group. High-risk patients were more responsive to immune checkpoint inhibitors (ICIs) and conventional chemotherapeutic agents. CONCLUSIONS: This cholesterol metabolism-related lncRNA signature can predict the prognosis of HCC patients and guide the clinical management of HCC patients, including immunotherapy.
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Multi-omic analysis of androgen-deprived human testes reveals Sertoli cell regulation and niche reprogramming.
Testis development and male fertility depend on androgens, yet the mechanisms underlying their regulation of adult human testicular function remain poorly defined due to ethical and technical constraints. To address this, we leverage androgen-deprived adult human testes as a spontaneous model and construct a comprehensive multi-omics atlas integrating single-nucleus RNA sequencing, single-cell ATAC-seq, and spatial transcriptomics. Our analyses highlight androgen-regulated transcription factors critical for Sertoli cell function and identify Neuregulin 2 (NRG2) as an androgen-dependent niche factor secreted by Sertoli cells that promotes spermatogonial proliferation both in vivo and in vitro. We further observe that androgen deprivation triggers ectopic expression of the Sertoli cell marker WT1 in the testicular interstitium, reprogramming a subset of interstitial cells toward a Sertoli-like transcriptomic state. Together, these findings uncover molecular mechanisms of androgen regulation in the adult human testes and provide a valuable resource for advancing therapies for androgen-related infertility and reproductive disorders.