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Mechanosensitive ion channel-related genes in hepatocellular carcinoma: Unraveling prognostic genes and their roles in drug resistance and immune modulation.
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and its etiology involves a complex interplay of genetic and environmental factors. Despite advancements in our understanding of HCC biology and the development of novel therapeutic strategies, the molecular mechanisms underlying its onset, progression, and resistance to therapy remain largely vague. This study aimed to investigate the role of mechanosensitive ion channel-related genes (MICRGs) in HCC, focusing on their potential as prognostic biomarkers and their involvement in immune modulation and drug resistance. METHODS: A comprehensive analysis was conducted using The Cancer Genome Atlas database to identify MICRGs that are upregulated in HCC. Gene expression profiling, bioinformatics tools, and functional experiments were employed to elucidate the role of these channels. In addition, protein-protein interaction (PPI) network analyses and enrichment analyses were performed to explore the biological significance of these genes. An immune cell infiltration analysis was also conducted to understand MICRG-related immune landscape. Single-cell RNA sequencing (scRNA-seq) data were utilized to identify MICRGs in different cell types within the HCC tissue. Deep-learning neural network analysis across patient cohorts was conducted to identify genes associated with sorafenib resistance. Knockdown experiments, cell viability assays, and apoptosis assays on HCC cell lines were performed to examine the role of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) in sorafenib resistance. RESULTS: The analysis identified a subset of MICRGs, including PIEZO1, that were significantly upregulated in HCC and associated with poor prognosis. The PPI network analysis revealed complex interactions among these genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses proposed the involvement of these genes in calcium signaling pathways. Immune cell infiltration analysis demonstrated distinct associations between MICRGs and various immune subpopulations, highlighting their potential roles in immune modulation. scRNA-seq data indicated the upregulation of MICRGs in various cell types in HCC tissues, particularly in endothelial cells and tumor-associated macrophages. Deep-learning neural network analysis across different patient cohorts identified PIEZO1 as a crucial regulator of sorafenib resistance in HCC, which was further validated by functional assays on HCC cell lines. CONCLUSIONS: This study provides evidence that MICRGs, particularly PIEZO1, take on crucial roles in HCC progression and drug resistance. The upregulation of PIEZO1 in HCC cells is associated with poor prognosis and resistance to sorafenib. These findings indicate that PIEZO1 could serve as a potential therapeutic target for overcoming drug resistance and a prognostic biomarker in HCC. Future studies should focus on validating these findings in larger patient cohorts and exploring the functional implications of targeting PIEZO1 in preclinical models.
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Single-cell transcriptomic landscape of sciatic nerve after transection injury.
Peripheral nerve injuries, particularly those affecting the sciatic nerve, often result in incomplete functional recovery due to the limited regenerative capacity of adult peripheral nerves. To elucidate the cellular and molecular mechanisms underlying nerve regeneration, we performed single-cell RNA sequencing (scRNA-seq) on rat sciatic nerve tissues at seven time points (Days 0, 1, 3, 5, 7, 10, and 14) following transection injury. Through unsupervised clustering, we identified four major cellular compartments-neurofibroblasts (NFs), glial cells (Glis), immune cells, and vascular cells-and delineated their dynamic trajectories during regeneration. Early responses were dominated by macrophage (Mac) and granulocyte infiltration (Day 1), followed by proliferative expansion of proliferating mesenchymal fibroblasts (NF5) and repair Schwann cells (Gli0) by Days 3-5. Vascular remodeling commenced from Day 7, while Glis progressively transitioned to mature myelinating states (Gli2/Gli5) by Day 14. Pseudotime analysis revealed subtype-specific reprogramming in both Macs and Glis, and cell-cell communication analysis uncovered key ligand-receptor interactions-particularly collagen and PTN signaling between Macs, NFs, and Glis. Bulk transcriptomic validation confirmed sustained and spatially distinct activation of the TGF-[Formula: see text] signaling pathway across cell types and anatomical locations. Comparative analysis with a sciatic nerve crush injury model revealed a stronger early immune response and delayed Gli recovery in transection injury, indicating a narrowed therapeutic window. Together, this work provides a time-resolved single-cell atlas of peripheral nerve regeneration, defines key regulatory circuits within the immune-NF-Gli axis, and identifies phase-specific therapeutic targets-such as early Mac heterogeneity, NF4-mediated matrix remodeling, and Schwann cell remyelination-for enhancing functional recovery following severe nerve injury.
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A molecular cell atlas of the human lung from single-cell RNA sequencing.
Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.
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Distinct roles of HMOX1 on tumor epithelium and macrophage for regulation of immune microenvironment in ovarian cancer.
BACKGROUND: Ferroptosis has been implicated in the regulation of the tumor immune environment; however, its precise effect on immune checkpoint inhibitors remains contradictory. OBJECTIVE: To elucidate the "double-edged sword effect" of a key ferroptosis-related factor in regulating the immune microenvironment. METHODS: This study utilized single-cell RNA sequencing (scRNA-seq) analysis to characterize the tumor microenvironment in ovarian cancer samples from immunotherapy cohorts. Following quality control and variable gene screening, data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), GENE EXPRESSION OMNIBUS (GEO), bulk, and spatial transcriptome databases were analyzed. The AddModuleScore_UCell function was employed for gene set scoring by evaluating the expression patterns of specific gene features in single-cell datasets, which were found to correlate with interactions between tumor cells and stromal cells, recognized as key contributors in the immunosuppressive milieu. Immunohistochemistry, western blot, and multiplex immunohistochemistry (mIHC) analyses were employed to explore the HMOX1/TGF-β1/PI3K/AKT/NF-κB(p65) signaling pathways. In vitro findings were further validated in a mouse model. The correlation between risk factors and progression-free survival (PFS) was analyzed using Cox regression and Kaplan-Meier methods. RESULTS: We demonstrated decreased expression of the ferroptosis-activating gene HMOX1 in ovarian cancer epithelial cells, while being upregulated in macrophages. Ovarian cancer (OV) epithelial cells with HMOX1 inhibition could secrete TGF-β1 to activate three macrophage subtypes: SPP1 + , FOLR2 + , and C1QC + via the PI3K/AKT/NF-κB (p65) pathway. The up-regulation of HMOX1 in macrophages also activated these three macrophage subtypes via the NF-κB pathway. Both pathways simultaneously inhibited Cytotoxic T Lymphocyte (CTL) activation and contributed to the immunosuppressive microenvironment of ovarian cancer, as demonstrated in both in vitro and in vivo models. Targeting HMOX1 alone, whether through activation or inhibition, was only effective in modulating a single pathway while simultaneously inducing negative feedback on the opposing pathway, demonstrating the "double-edged sword effect" of HMOX1 in regulating the immune microenvironment. CONCLUSION: Overall, we proposed and validated two strategies targeting HMOX1 to improve the efficacy of PD-1 inhibitors, and confirmed that HMOX1, TGF-β1, SPP1, FOLR2, and C1QC could be used to construct models predicting the efficacy of immune checkpoint inhibitors.
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SPINK1-driven cellular heterogeneity and interaction networks in intrahepatic cholangiocarcinoma revealed by integrated multi-omics analysis.
INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous and aggressive malignancy with poor prognosis and limited treatment options. The lack of precise molecular classification and incomplete understanding of the tumor microenvironment (TME) impede therapeutic development. OBJECTIVES: This study aims to dissect the cellular heterogeneity and intercellular interactions in ICC, with a particular focus on SPINK1-overexpressing epithelial subsets. We sought to determine the role of SPINK1 in modulating immune cell recruitment and tumor metabolism, and to evaluate its clinical relevance. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on human ICC tumors and adjacent normal tissues to construct a transcriptomic atlas. Integrative proteomic analysis, transwell assays, co-culture systems, and functional perturbation experiments (SPINK1 knockdown and ASCT2 inhibition) were conducted to explore epithelial-macrophage interactions and metabolic dynamics. RESULTS: ScRNA-seq identified a SPINK1-overexpressing epithelial subcluster enriched in ICC tumors. High SPINK1 expression correlated with significantly shorter patient survival. SPINK1-overexpressing epithelial subcluster secretes CCL20, which recruits lipid-associated macrophages (LAMs). This effect was reversed by CCL20 neutralizing antibodies. In co-culture, LAMs increased intracellular glutamine levels in SPINK1-overexpressing epithelial subcluster, promoting proliferation. Disruption of SPINK1 expression or glutamine transport abolished this metabolic support. CONCLUSION: Our findings uncover a novel SPINK1-CCL20-LAMs axis that orchestrates immune recruitment and metabolic reprogramming in ICC. SPINK1 facilitates tumor growth by establishing a glutamine-rich microenvironment via LAMs. These insights highlight SPINK1 as a potential therapeutic target and prognostic biomarker in ICC.
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Multiomics identifies tumor-intrinsic SREBP1 driving immune exclusion in hepatocellular carcinoma.
Immune checkpoint inhibitors (ICI) have improved patient outcomes in hepatocellular carcinoma (HCC); however, most patients do not experience durable benefit. The non-T cell-inflamed tumor microenvironment, characterized by limited CD8+ T-cell infiltration, reduced dendritic cell function, and low interferon-γ-associated gene expression, is associated with a lower likelihood of response to ICI. To nominate new therapeutic targets for overcoming ICI resistance in HCC, we conducted a large-scale multiomic analysis on 900+human specimens (RNA sequencing (RNA-seq), proteomics) and 31 tumor single-cell (sc) RNA-seq samples, with tissue validation through imaging mass cytometry (IMC) and spatial lipidomics by matrix-assisted laser desorption/ionization (MALDI), with experimental investigation by in vitro CD8+ T-cell recruitment and macrophage polarization functional assays using three-dimensional (3D) co-culture models. We discovered 32 oncogenic pathways associated with immune exclusion, with sterol regulatory element binding protein 1 (SREBP1, encoded by SREBF1) as a hub regulator. scRNA-seq analysis showed that SREBP1 signaling is associated with enriched lipid biogenesis pathways in tumor cells, elevated immunosuppressive markers in macrophages, and diminished CD8+ T-cell infiltration. Integration of IMC and MALDI images revealed distinct lipid species differentially abundant in tumor regions with low versus high CD8+ T cell infiltration. Functional studies in a 3D in vitro tumor-immune co-culture system demonstrated that CRISPR-mediated SREBF1 knockout (KO) in HepG2 cells reduced monocyte recruitment, decreased expression of the protumorigenic CD206 marker in macrophages, and enhanced CD8+ T-cell migration compared with wild-type (WT) (p<0.0001). RNA-seq of SREBF1 KO versus WT tumor cells confirmed suppression of lipid biosynthesis genes.Our findings nominate an atlas of tumor-intrinsic drivers of immune exclusion, particularly SREBP1 via pro-tumorigenic macrophage (M2-like) reprogramming. These pathways may represent novel therapeutic targets to enhance antitumor immunity and deserve further study as targeted therapy candidates to enhance ICI in HCC.
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Single-cell transcriptomics analysis reveals that the tumor-infiltrating B cells determine the indolent fate of papillary thyroid carcinoma.
OBJECTIVE: Active surveillance (AS) offers a viable alternative to surgical intervention for the management of indolent papillary thyroid carcinoma (PTC), helping to minimize the incidence of unnecessary treatment. However, the broader adoption of AS is hindered by the need for more reliable diagnostic markers. This study aimed to identify the differences between indolent and progressive PTC and find new targets for biomarker development and therapeutic strategies. METHODS: We used single-cell RNA sequencing (scRNA-seq) to analyze cellular differences in 10 early-stage PTC tumors. Findings were validated in an additional 25 tumors using cell co-culture, migration assays, immunofluorescence staining, flow cytometry, and analysis of data from The Cancer Genome Atlas (TCGA). RESULTS: Tumor-infiltrating B cells (TIL-B), particularly germinal center B cells (GC-B), were more abundant in indolent PTC. These cells suppressed thyroid cell proliferation in both indolent and progressive cases, though indolent PTC had a higher capacity to recruit peripheral B cells. In indolent cases, TIL-B cells showed increased proliferation and formed clusters within tertiary lymphoid structures (TLS). PTPRC-CD22 interactions were identified as potential drivers of TIL-B cell proliferation. Markers linked to GC-B cells, such as LMO2, were highlighted as potential diagnostic and prognostic indicators for indolent PTC. CONCLUSION: This study provides insights into the cellular landscape of early-stage PTC, revealing distinct tumor and immune microenvironment features in indolent and progressive cases. These findings advance the understanding of indolent PTC biology and support the development of reliable diagnostic and prognostic biomarkers.
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Spatial transcriptomics and the kidney.
PURPOSE OF REVIEW: The application of spatial transcriptomics technologies to the interrogation of kidney tissue is a burgeoning effort. These technologies share a common purpose in mapping both the expression of individual molecules and entire transcriptomic signatures of kidney cell types and structures. Such information is often superimposed upon a histologic image. The resulting datasets are readily merged with other imaging and transcriptomic techniques to establish a spatially anchored atlas of the kidney. This review provides an overview of the various spatial transcriptomic technologies and recent studies in kidney disease. Potential applications gleaned from the interrogation of other organ systems, but relative to the kidney, are also discussed. RECENT FINDINGS: Spatial transcriptomic technologies have enabled localization of whole transcriptome mRNA expression, correlation of mRNA to histology, measurement of in situ changes in expression across time, and even subcellular localization of transcripts within the kidney. These innovations continue to aid in the development of human cellular atlases of the kidney, the reclassification of disease, and the identification of important therapeutic targets. SUMMARY: Spatial localization of gene expression will complement our current understanding of disease derived from single cell RNA sequencing, histopathology, protein immunofluorescence, and electron microscopy. Although spatial technologies continue to evolve rapidly, their importance in the localization of disease signatures is already apparent. Further efforts are required to integrate whole transcriptome and subcellular expression signatures into the individualized assessment of human kidney disease.
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Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle.
In a human menstrual cycle the endometrium undergoes remodeling, shedding and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, our understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single-cell resolution across the menstrual cycle, resolving cellular heterogeneity in multiple dimensions. We profiled the behavior of seven endometrial cell types, including a previously uncharacterized ciliated cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that the human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with a widespread decidualization feature in the stromal fibroblasts. Our study provides a high-resolution molecular and cellular characterization of human endometrial transformation across the menstrual cycle, providing insights into this essential physiological process.
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Integrative analysis confirms TPX2 as a novel biomarker for clinical implication, tumor microenvironment, and immunotherapy response across human solid tumors.
Targeting Protein for Xenopus Kinesin Like Protein 2 (TPX2) serves as a microtubule associated protein for the regulation of spindle assembly and tumorigenesis. We aim to investigate the prognostic and immunological role of TPX2 in pan-cancer. TCGA database, Tumor Immune Single-cell Hub (TISCH), and Human Protein Atlas (HPA) were retrieved to evaluate the expression pattern of TPX2 as well as its diagnostic and prognostic value in solid tumors. Genomic alterations of TPX2 were assessed with cBioPortal database. In vitro experiments in lung adenocarcinoma (LUAD) were performed to confirm the potential role of TPX2. Overexpression of TPX2 was found in 22 types of cancers, and was positively related with copy number variations (CNV) and negative with methylation. Up-regulated TPX2 could predict worse outcomes in the majority of cancers. Single-cell analysis revealed that TPX2 was mainly distributed in malignant cells (especially in glioma) and proliferating T cells. Genomic alteration of TPX2 was common in different types of tumors, while with prognostic value in two types of cancers. Additionally, significant correlations were found between TPX2 expression and tumor microenvironment (including stromal cells and immune cells) as well as immune related genes across cancer types. Drug sensitivity analysis revealed that TPX2 could predict response to chemotherapy and immunotherapy. Functional analyses demonstrated close relationship of TPX2 with immune function and malignant phenotypes. Finally, it was confirmed that knockdown of TPX2 could reduce proliferation and migration ability of LUAD cells. In summary, TPX2 could serve as a diagnostic and prognostic biomarker and a potential immunotherapy marker.