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Adrenomedullin orchestrates treatment resistance in hepatocellular carcinoma via immune microenvironment remodeling.
BACKGROUND: Hepatocellular carcinoma (HCC) displays marked cellular heterogeneity and immune microenvironment complexity that fundamentally influence transcatheter arterial chemoembolization (TACE) treatment responses and patient outcomes. Deciphering the molecular architecture underlying therapy resistance remains essential for advancing precision oncology in HCC management. METHODS: We integrated four single-cell RNA sequencing cohorts with bulk transcriptomic datasets and longitudinal clinical annotations from The Cancer Genome Atlas Liver Hepatocellular Carcinoma database and Gene Expression Omnibus repositories to perform multidimensional analyses. Computational frameworks including single-cell Phenotype Associated Score (scPAS), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and Single-Cell Regulatory Network Inference and Clustering (SCENIC) were deployed to identify resistance-linked cellular subpopulations and pivotal regulatory modules. Functional validation employed adrenomedullin (ADM)-depleted Huh7 cellular models and xenograft tumor-bearing mouse systems, with mechanistic interrogation via Western immunoblotting, quantitative reverse transcription polymerase chain reaction, and Kaplan-Meier survival estimation to confirm ADM biological functions and clinical relevance. RESULTS: We identified a TACE-resistant malignant cell subset (scPAS+) characterized by pronounced activation of glycolytic, hypoxic, and epithelial-mesenchymal transition pathways alongside overexpression of resistance-conferring genes including LINC00221, hexokinase 2, and alpha-fetoprotein. This cellular phenotype demonstrated robust associations with TACE non-responsiveness, sorafenib cross-resistance, and abbreviated patient survival. Patient stratification based on scPAS + signature genes delineated two distinct molecular subgroups: the scPAS + -enriched cohort exhibited marked TACE refractoriness, elevated sorafenib failure rates, immunosuppressive microenvironmental architecture, and diminished 5-year survival probability. Mechanistic investigations established ADM as a critical driver orchestrating this resistance phenotype. ADM depletion attenuated Huh7 cell proliferative capacity, migratory potential, and invasive behavior, reduced xenograft tumor burden in murine models, and substantially potentiated sorafenib antitumor efficacy. CONCLUSION: This study delineates an ADM-driven TACE-resistant HCC cellular subtype (scPAS+) that functions simultaneously as a prognostic biomarker and actionable therapeutic target for circumventing treatment resistance.
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Cellular and Molecular Atlas of Peripheral Blood Mononuclear Cells from a Pregnant Woman After Recovery from COVID-19.
OBJECTIVE: This study aimed to investigate the immune response of a pregnant woman who recovered from the coronavirus disease 2019 (COVID_RS) by using single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and to analyze the properties of different immune cell subsets. METHODS: PBMCs were collected from the COVID_RS patient at 28 weeks of gestation, before a cesarean section. The PBMCs were then analyzed using single-cell RNA sequencing. The transcriptional profiles of myeloid, T, and natural killer (NK) cell subsets were systematically analyzed and compared with those of healthy pregnant controls from a published single-cell RNA sequencing data set. RESULTS: We identified major cell types such as T cells, B cells, NK cells, and myeloid cells in the PBMCs of our COVID_RS patient. The increase of myeloid and B cells and decrease of T cells and NK cells in the PBMCs in this patient were quite distinct compared with that in the control subjects. After reclustering and Augur analysis, we found that CD16 monocytes and mucosal-associated invariant T (MAIT) cells were mostly affected within different myeloid, T, and NK cell subtypes in our COVID_RS patient. The proportion of CD16 monocytes in the total myeloid population was increased, and the frequency of MAIT cells in the total T and NK cells was significantly decreased in the COVID-RS patient. We also observed significant enrichment of gene sets related to antigen processing and presentation, T-cell activation, T-cell differentiation, and tumor necrosis factor superfamily cytokine production in CD16 monocytes, and enrichment of gene sets related to antigen processing and presentation, response to type II interferon, and response to virus in MAIT cells. CONCLUSION: Our study provides a single-cell resolution atlas of the immune gene expression patterns in PBMCs from a COVID_RS patient. Our findings suggest that CD16-positive monocytes and MAIT cells likely play crucial roles in the maternal immune response against severe acute respiratory syndrome coronavirus 2 infection. These results contribute to a better understanding of the maternal immune response to severe acute respiratory syndrome coronavirus 2 infection and may have implications for the development of effective treatments and preventive strategies for the coronavirus disease 2019 in pregnant women.
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Comprehensive analysis to identify PUS7 as a prognostic biomarker from pan-cancer analysis to osteosarcoma validation.
AIM: Pseudouridylation has demonstrated the potential to control the development of numerous malignancies. PUS7(Pseudouridine Synthase 7) is one of the pseudouridine synthases, but the literature on this enzyme is limited to several cancer types. Currently, no investigation has been performed on the systematic pan-cancer analysis concerning PUS7 role in cancer diagnosis and prognosis. METHODS: Employing public databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), Human Protein Atlas (HPA), UALCAN and Tumor Immune Single-cell Hub (TISCH), this work investigated the PUS7 carcinogenesis in pan-cancer. Differential expression analysis, prognostic survival analysis and biological function were systematically performed. Furthermore, PUS7 potential as an osteosarcoma biomarker for diagnosis and prognosis was assessed in this study. RESULTS: The findings indicated that PUS7 was overexpressed in the majority of malignancies. High PUS7 expression contributed to the poor prognosis among 11 cancer types, including Adrenocortical Cancer (ACC), Bladder Cancer (BLCA), Liver Cancer (LIHC), Kidney Papillary Cell Carcinoma (KIRP), Mesothelioma (MESO), Lower Grade Glioma (LGG), Kidney Chromophobe (KICH), Sarcoma (SARC), osteosarcoma (OS), Pancreatic Cancer (PAAD), and Thyroid Cancer (THCA). In addition, elevated PUS7 expression was linked to advanced TNM across multiple malignancies, including ACC, BLCA, KIRP, LIHC and PAAD. The function enrichment analysis revealed that PUS7 participates in E2F targets, G2M checkpoint, ribosome biogenesis, and rRNA metabolic process. Moreover, PUS7 is also a reliable biomarker and a potential therapeutic target for osteosarcoma. CONCLUSIONS: In summary, PUS7 is a putative pan-cancer biomarker that reliably forecasts cancer patients' prognosis. In addition, this enzyme regulates the cell cycle, ribosome biogenesis, and rRNA metabolism. Most importantly, PUS7 possibly regulates osteosarcoma initiation and progression.
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Specification of neuronal subtypes in the spiral ganglion begins prior to birth in the mouse.
The afferent innervation of the cochlea is comprised of spiral ganglion neurons (SGNs), which are characterized into four subtypes (Type 1A, B, and C and Type 2). However, little is known about the factors and/or processes that determine each subtype. Here, we present a transcriptional analysis of approximately 5,500 single murine SGNs collected across four developmental time points. All four subtypes are transcriptionally identifiable prior to the onset of coordinated spontaneous activity, indicating that the initial specification process is under genetic control. Trajectory analysis indicates that SGNs initially split into two precursor types (Type 1A/2 and Type 1B/C), followed by subsequent splits to give rise to four transcriptionally distinct subtypes. Differential gene expression, pseudotime, and regulon analyses were used to identify candidate transcription factors which may regulate the subtypes specification process. These results provide insights into SGN development and comprise a transcriptional atlas of SGN maturation across the prenatal period.
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Single-cell transcriptomic atlas of blood and lung from mice infected with SARS-CoV-2 revealing distinct virulence characteristics between prototype and Omicron BA.1 strain.
The markedly reduced pathogenicity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron variant in comparison to earlier strains has raised critical questions regarding its underlying mechanisms. To elucidate the host immune responses driving these differences, we performed single-cell transcriptomic profiling of lung and blood samples from human angiotensin-converting enzyme 2 (hACE2) transgenic mice infected with either the SARS-CoV-2 prototype strain or the Omicron BA.1 variant at 5 days post-inoculation. Both strains induced a reduction in lung cell numbers, with capillary endothelial cells showing the highest number of differentially expressed genes (DEGs). Shared transcriptional responses included upregulation of chemokine (e.g. Gnaq, Lyn, Ccl5) and IL-17 signaling pathways. Notably, Omicron BA.1 infection resulted in downregulation of Txnip, a key gene involved in oxidative stress responses. Genes associated with neutrophil granules and pro-inflammatory functions (Mmp8, S100a8, S100a9) were also downregulated, whereas wound healing pathways were upregulated in immature neutrophils. Additionally, Omicron BA.1 altered gene expression associated with neutrophil migration from blood to lung, and decreased the activation of cell chemotaxis, cytokine-mediated signaling, IL-17 and NF-κB pathways in pro-inflammatory monocytes and pulmonary interstitial macrophages. These findings highlight distinct immunological signatures contributing to the attenuated pathogenicity of Omicron BA.1, particularly through the modulation of neutrophil and monocyte-macrophage responses.
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Integrated multiomics analysis reveals the molecular features and crucial regulators of hair follicles in yak (Bos grunniens).
Yak is a unique bovine species that adapts to the extreme climate of the Qinghai-Tibet Plateau in part owing to its dense skin coat. Despite its essential role in cold adaptation, the genetic basis of hair follicle structure and growth has not been extensively studied in this iconic animal. In the present study, we construct a single-cell atlas of hair follicle (HF) cells from yak and taurine cattle and examine differences in their cellular composition and gene expression. Among the 14 cell types identified in HFs, the dermal papilla (DP) displays the most dramatic differences between cattle and yak. Detailed analysis reveals that the genes in the WNT signaling pathway are differentially expressed in the dermal papilla (DP) cells of yak. Using primary cultures of DP cells, we reveal that the inhibition or activation of WNT/β-Catenin dramatically alters cell cycle progression and autophagy. In complimentary with the ATAC-seq data, we show that SOX4 is directly associated with the promoters of WNT1 and WNT3A. Interestingly, increased autophagy regulates the expression of SOX4/WNT/β-Catenin to promote the proliferation of DP cells in yak. Together, these results reveal the molecular signature of coat adaptation at the single-cell transcription level and provide a new understanding of animal adaptation to extreme environments.
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Dendritic Cell-Related Immune Marker CD1C for Predicting Prognosis and Immunotherapy Opportunities of Lung Adenocarcinoma Patients.
Lung adenocarcinoma (LUAD) is the most frequent type of lung cancer with a high mortality rate. Here, we aim to explore novel immune-related biomarkers for LUAD patients. Datasets, mRNA expression profiles, and clinical data concerned with LUAD were obtained from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), respectively. Differential expression analysis was performed to obtain differentially expressed genes (DEGs). Based on DEGs, we conducted functional enrichment analyses. Subsequently, Kaplan‑Meier (KM) was performed to analyze survival differences among different groups. Furthermore, immune cell infiltration proportion was calculated by CIBERSORT and TIMER. The relationship between gene and immune response was analyzed using Tumor Immune System Interactions (TISIDB) database. Finally, Pearson correlation analysis was performed between CD1C and six immune checkpoints. We identified dendritic cells (DCs)-related expression profiles from four LUAD samples. DCs' immune marker CD1C in LUAD was selected by univariate Cox regression analysis. Low CD1C expression patients had a poor prognosis. A total of 332 DEGs were identified in high and low CD1C expression groups, which primarily enriched in 348 GO terms and 30 KEGG pathways. There were significant differences in the infiltration proportion of 17 immune cells between high and low CD1C expression groups. Most immunomodulators, chemokines, and chemokine receptors were positively associated with CD1C expression. Six immune checkpoints were also positively correlated with CD1C expression. DCs related immunomarker CD1C probably plays a pivotal part in prognosis and immunotherapy of LUAD via a joint analysis of single-cell and bulk sequencing data.
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ACKR3 in olfactory glia cells shapes the immune defense of the olfactory mucosa.
Barrier-forming olfactory glia cells, termed sustentacular cells, play important roles for immune defense of the olfactory mucosa, for example as entry sites for SARS-CoV-2 and subsequent development of inflammation-induced smell loss. Here we demonstrate that sustentacular cells express ACKR3, a chemokine receptor that functions both as a scavenger of the chemokine CXCL12 and as an activator of alternative signaling pathways. Differential gene expression analysis of bulk RNA sequencing data obtained from WT and ACKR3 conditional knockout mice revealed upregulation of genes involved in immune defense. To map the regulated genes to the different cell types of the olfactory mucosa, we employed biocomputational methods utilizing a single-cell reference atlas. Transcriptome analysis, PCR and immunofluorescence identified up-regulation of NF-κB-related genes, known to amplify inflammatory signaling and to facilitate leukocyte transmigration, in the gliogenic lineage. Accordingly, we found a marked increase in leukocyte-expressed genes and confirmed leukocyte infiltration into the olfactory mucosa. In addition, lack of ACKR3 led to enhanced expression and secretion of early mediators of immune defense by Bowman's glands. As a result, the number of apoptotic cells in the epithelium was decreased. In conclusion, our research underlines the importance of sustentacular cells in immune defense of the olfactory mucosa. Moreover, it identifies ACKR3, a druggable G protein-coupled receptor, as a promising target for modulation of inflammation-associated anosmia.
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Multi-omics landscape analysis reveals the pan-cancer association of arginine biosynthesis genes with tumor immune evasion and therapy resistance.
BACKGROUND: The metabolism of arginine, a conditionally essential amino acid, plays a crucial role in cancer progression and prognosis. However, a more detailed understanding of the influence of arginine biosynthesis genes in cancer is currently unavailable. METHODS: We performed an integrative multi-omics analysis using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to determine the characteristics of these genes across multiple cancer types. To measure the overall activity of arginine biosynthesis genes in cancer, we calculated arginine biosynthesis scores based on gene expression. RESULTS: Our results indicated that the arginine biosynthesis score was negatively correlated with immune-related pathways, immune infiltration, immune checkpoint expression, and patient prognosis, and single-cell data further clarified that patients with high arginine biosynthesis scores showed a reduced proportion of T and B cells in an immune desert tumor microenvironment and were insensitive to immunotherapy. We also identified several potential drugs through the Cancer Therapeutic Response Portal (CTRP) and Genomics of Drug Sensitivity in Cancer (GDSC) databases that could target arginine biosynthesis genes and potentially improve the response rate to immunotherapy in patients with a high arginine biosynthesis fraction. CONCLUSION: Overall, our analyses emphasize that arginine biosynthesis genes are associated with immune evasion in several cancers. Targeting these genes may facilitate more effective immunotherapy.
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Single nucleus multiomic atlas of human dorsal root ganglia reveals the contribution of non-neuronal cell types to pain.
Sensory neurons residing in dorsal root ganglia (DRG) transmit sensory information such as pain, itch, touch, pressure and bodily position to the central nervous system. The activity of sensory neurons is regulated by non-neuronal cell types in the DRG, including satellite glial cells (SGCs) and fibroblasts. Dysregulated gene expression in DRG cells contributes to sensory nervous system disorders such as chronic pain and itch. Understanding the genetic underpinnings of these conditions requires dissecting transcriptional regulation in human DRG (hDRG). In this study, we profiled transcriptomic and chromatin accessibility landscapes from postmortem hDRG samples at single-cell level. We demonstrate that sequencing depth significantly impacts downstream analysis, with deeper sequencing yielding more detected cells and features, improved data integration, refined clustering and annotation, and more accurate scientific interpretations. We identified nine major cell types, defined their molecular signatures, and mapped cis-regulatory landscapes. Integration of gene expression with chromatin accessibility enabled peak-gene association and transcriptional network analyses, revealing transcription factors, their target genes, and their regulatory elements. This approach uncovered cell types, genes, and cis-regulatory regions potentially driving pain conditions. Our unbiased genome-wide analysis confirmed known pain-related genes and highlighted novel candidates. These findings provide new insight into molecular mechanisms and candidate cell types involved in pain. Importantly, our results demonstrate that non-neuronal cell types, including endothelial cells, fibroblasts, macrophages, and SGCs, play critical roles in pain pathogenesis and should be investigated as therapeutic targets.