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A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target.
Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work investigated the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.
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Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding.
OBJECTIVES: The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation. METHODS: We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice. RESULTS: We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake. CONCLUSIONS: These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.
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Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.
To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.
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The critical role of PDGFRa + Sca1 + fibroblasts in angiogenesis and vascular repair in the corpus cavernosum.
BACKGROUND: Erectile dysfunction (ED) is an important cause of reduced quality of life for men and their partners. A common pathological feature across various types of ED, including diabetes mellitus-induced ED (DMED) and bilateral cavernous nerve injury-induced ED (CNIED), is the loss of endothelial cells (ECs) and smooth muscle cells (SMCs) in the corpus cavernosum (CC). Stem cell-based therapies have garnered attention due to their potential to differentiate into specialized cell types, offering promise for the treatment of ED. Fibroblasts (FBs), the most abundant cell type in the CC, have raised considerable interest in recent years. However, the functional role of FBs in the progression of ED remains unclear. METHODS: We established DMED and CNIED animal models and performed single-cell RNA sequencing (scRNA-seq) to analyze cell subsets within the pathological environments of these two ED types. To further investigate the cellular landscape, we combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify specific FB subsets in the CC. RESULTS: scRNA-seq revealed a distinct subset of FBs that overexpress both Sca1 and PDGFRa. CytoTRACE analysis and Gene Set Enrichment Analysis (GSEA) indicated that PDGFRa + Sca1 + FBs may be associated with angiogenesis and possess the potential to differentiate into ECs and SMCs. Immunofluorescence analysis confirmed that PDGFRa + Sca1 + FBs were localized to the vessel walls, with co-localization of Sca1 and PDGFRa observed with markers for SMCs and ECs. Our findings shed light on the role of PDGFRa + Sca1 + FBs in the CC, demonstrating their involvement in angiogenesis and vascular repair. The depletion of these FBs in disease conditions may contribute to the exhaustion of ECs and SMCs, providing new insights into the pathogenesis of ED. CONCLUSION: These results open potential avenues for novel therapeutic strategies aimed at targeting PDGFRa + Sca1 + FBs to restore vascular function in ED.
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Single-Cell Atlas Reveals Complexity of the Immunosuppressive Microenvironment of Initial and Recurrent Glioblastoma.
The Glioblastoma (GBM) immune microenvironment plays a critical role in tumor development, progression, and prognosis. A comprehensive understanding of the intricate milieu and its interactions remains unclear, and single-cell analysis is crucially needed. Leveraging mass cytometry (CyTOF), we analyzed immunocytes from 13 initial and three recurrent GBM samples and their matched peripheral blood mononuclear cells (pPBMCs). Using a panel of 30 markers, we provide a high-dimensional view of the complex GBM immune microenvironment. Hematoxylin and eosin staining and polychromatic immunofluorescence were used for verification of the key findings. In the initial and recurrent GBMs, glioma-associated microglia/macrophages (GAMs) constituted 59.05 and 27.87% of the immunocytes, respectively; programmed cell death-ligand 1 (PD-L1), T cell immunoglobulin domain and mucin domain-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), interleukin-10 (IL-10) and transforming growth factor-β (TGFβ) demonstrated different expression levels in the GAMs among the patients. GAMs could be subdivided into different subgroups with different phenotypes. Both the exhausted T cell and regulatory T (Treg) cell percentages were significantly higher in tumors than in pPBMCs. The natural killer (NK) cells that infiltrated into the tumor lesions expressed higher levels of CXC chemokine receptor 3 (CXCR3), as these cells expressed lower levels of interferon-γ (IFNγ). The immune microenvironment in the initial and recurrent GBMs displayed similar suppressive changes. Our study confirmed that GAMs, as the dominant infiltrating immunocytes, present great inter- and intra-tumoral heterogeneity and that GAMs, increased exhausted T cells, infiltrating Tregs, and nonfunctional NK cells contribute to local immune suppressive characteristics. Recurrent GBMs share similar immune signatures with the initial GBMs except the proportion of GAMs decreases.
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Downregulated Acetyl-CoA Acyltransferase 2 Promoted the Progression of Hepatocellular Carcinoma and Participated in the Formation of Immunosuppressive Microenvironment.
BACKGROUND: The aim of this study is to explore the role of acetyl-CoA acyltransferase 2 (ACAA2) in the progression of hepatocellular carcinoma (HCC). METHODS: Bulk RNA data and single-cell RNA data were acquired from The Cancer Genome Atlas and Gene Expression Omnibus. Both in vitro and in vivo studies were used to determine the effect of ACAA2 on the progression of HCC, and RNA sequencing analysis was performed to explore the mechanism. RESULTS: We found downregulation of ACAA2 was involved in the malignant progression of HCC. The patient with low ACAA2 level had an immunosuppressive microenvironment in the HCC and predicted to have a poor prognosis. Decreased ACAA2 facilitated HCC proliferation and metastasis by activating the nuclear factor-κB (NFκB) signaling pathway. And increased CXCL1 induced by NFκB signaling pathway might be responsible for low level of ACAA2 related immunosuppressive microenvironment. Furthermore, the expression of ACAA2 was also detected in immune cells. The expression of ACAA2 in CD4+TCF7+T, CD4+FOXP3+T, CD8+GZMK+T, and CD8+KLRD1+T cells was inversely correlated with the composition of CD8+PDCD1+T cells in HCC. This effect might be due to the CCL5-CCRs and HLA-E-KLRCs ligand-receptor networks. CONCLUSION: In a conclusion, downregulated ACAA2 promoted the progression of hepatocellular carcinoma and might be participated in the formation of immunosuppressive microenvironment. ACAA2 could be served as a favorable indicator for the prognosis of HCC and an ideal biomarker for immunotherapy.
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Single-cell transcriptomic analysis in a mouse model deciphers cell transition states in the multistep development of esophageal cancer.
Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8+ response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.
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Peroxisome proliferator-activated receptors signature reveal the head and neck squamous cell carcinoma energy metabolism phenotype and clinical outcome.
BACKGROUND: Peroxisome proliferator activating receptors (PPARs) are important regulators of nuclear hormone receptor function, and they play a key role in biological processes such as lipid metabolism, inflammation and cell proliferation. However, their role in head and neck squamous cell carcinoma (HNSC) is unclear. METHODS: We used multiple datasets, including TCGA-HNSC, GSE41613, GSE139324, PRJEB23709 and IMVigor, to perform a comprehensive analysis of PPAR-related genes in HNSC. Single-cell sequencing data were preprocessed using Seurat packets, and intercellular communication was analyzed using CellChat packets. Functional enrichment analysis of PPAR-related genes was performed using ClusterProfile and GSEA. Prognostic models were constructed using LASSO and Cox regression models, and immunohistochemical analyses were performed using human protein mapping (The Human Protein Atlas). RESULTS: Our single-cell RNA sequencing analysis revealed distinct cell populations in HNSC, with T cells having the most significant transcriptome differences between tumors and normal tissues. The PPAR features were higher in most cell types in tumor tissues compared with normal tissues. We identified 17 PPAR-associated differentially expressed genes between tumors and normal tissues. A prognostic model based on seven PPAR-associated genes was constructed with high accuracy in predicting 1, 2 and 3 year survival in patients with HNSC. In addition, patients with a low risk score had a higher immune score and a higher proportion of T cells, CD8+ T cells and cytotoxic lymphocytes. They also showed higher immune checkpoint gene expression, suggesting that they might benefit from immunotherapy. PPAR-related genes were found to be closely related to energy metabolism. CONCLUSIONS: Our study provides a comprehensive understanding of the role of PPAR related genes in HNSC. The identified PPAR features and constructed prognostic models may serve as potential biomarkers for HNSC prognosis and treatment response. In addition, our study found that PPAR-related genes can differentiate energy metabolism and distinguish energy metabolic heterogeneity in HNSC, providing new insights into the molecular mechanisms of HNSC progression and therapeutic response.
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Single-cell Profiling of Reprogrammed Human Neural Stem Cells Unveils High Similarity to Neural Progenitors in the Developing Central Nervous System.
BACKGROUND: Similar to induced pluripotent cells (iPSCs), induced neural stem cells (iNSCs) can be directly converted from human somatic cells such as dermal fibroblasts and peripheral blood monocytes. While previous studies have demonstrated the resemblance of iNSCs to neural stem cells derived from primary sources and embryonic stem cells, respectively, a comprehensive analysis of the correlation between iNSCs and their physiological counterparts remained to be investigated. METHODS: Nowadays, single-cell sequencing technologies provide unique opportunities for in-depth cellular benchmarking of complex cell populations. Our study involves the comprehensive profiling of converted human iNSCs at a single-cell transcriptomic level, alongside conventional methods, like flow cytometry and immunofluorescence stainings. RESULTS: Our results show that the iNSC conversion yields a homogeneous cell population expressing bona fide neural stem cell markers. Extracting transcriptomic signatures from published single cell transcriptomic atlas data and comparison to the iNSC transcriptome reveals resemblance to embryonic neuroepithelial cells of early neurodevelopmental stages observed in vivo at 5 weeks of development. CONCLUSION: Our data underscore the physiological relevance of directly converted iNSCs, making them a valuable in vitro system for modeling human central nervous system development and establishing translational applications in cell therapy and compound screening.
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Substantially Altered Local and Systemic Immunity in Ischemia-Free Versus Conventional Liver Transplantation.
Ischemia-free liver transplant (IFLT) has been developed to reduce ischemia-reperfusion injury (IRI). This study aims to investigate how this procedure impacts local and systemic immunity compared to conventional liver transplantation (CLT). Immunohistochemistry, immunofluorescence staining, single-cell RNA sequencing (scRNA-seq), and multiplex cytokine are used to illustrate distinct local and systemic immunity. In contrast to CLT, IFLT reduces neutrophil infiltration and neutrophil extracellular trap formation in grafts. By constructing an immune cell chimerism atlas, we reveal that IFLT reduces recipient-derived monocyte infiltration by suppressing ANXA1-FPR1 signaling through the STAT3-HIF-1α pathway, thereby attenuating inflammatory responses in graft monocytes. Additionally, IFLT confers graft protection by upregulating HMOX1 expression in monocytes and macrophages. Peripherally, IFLT significantly reduces the expression of MHC II molecules in circulating monocytes. Accordingly, CD8+ effector T cell composition, T helper 1 (Th1) and Th17 cytokine levels are reduced, while regulatory T cell (Treg) composition and Th2 cytokine levels are increased in IFLT versus CLT recipients. These results show that IFLT profoundly affects local and systemic immunity in liver transplantation. Recipient-circulating monocytes might play a key role in the interaction between graft IRI and allograft rejection.