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Integrative multiomics dissection of LSM7 as a prognostic biomarker and therapeutic target in hepatocellular carcinoma.
ObjectiveHepatocellular carcinoma (HCC) has a poor prognosis, necessitating novel biomarkers. The role of LSM7 (Like-Sm protein 7), an RNA-binding protein, in HCC remains unclear.MethodsWe employed a multiomics strategy using transcriptomic data from TCGA, GTEx, GEO, and ICGC to evaluate LSM7's expression and prognostic value. A protein-protein interaction (PPI) network was constructed via STRING, followed by Gene Ontology/KEGG/Gene Set Enrichment Analysis (GSEA) functional enrichment analysis. The relationship between LSM7 and the immune infiltration landscape was assessed using single-sample GSEA (ssGSEA) and the TISCH single-cell database. Drug sensitivity was analyzed using Genomics of Drug Sensitivity in Cancer, and structure-based virtual screening was performed on the ZINC library to identify potential LSM7 inhibitors. Key findings were validated in clinical samples and MHCC97H cells and Huh-7 cells using Western blot, IHC, and MTT assays.ResultsLSM7 was significantly overexpressed in HCC, correlating with adverse clinicopathological features (higher histological grade, elevated AFP levels, vascular invasion) and shorter overall survival, identifying it as an independent risk factor. Functionally, LSM7 was implicated in processes such as hormone regulation. Immune analysis revealed that high LSM7 expression was associated with altered immune cell abundance, upregulation of immune checkpoints, and a higher Tumor Immune Dysfunction and Exclusion score, suggesting a role in immune evasion. The high-LSM7 group showed increased sensitivity to drugs like sorafenib. Virtual screening identified Velpatasvir as a top LSM7-targeting candidate, with in vitro validation confirming that it inhibits MHCC97H cells and Huh-7 cells proliferation and downregulates LSM7 protein in a concentration- and time-dependent manner.ConclusionsBy integrating multiomics strategy and experimental validation, this study suggests that LSM7 may play a role in HCC progression and influence the tumor immune microenvironment. LSM7 may serve as a potential biomarker and therapeutic target, and Velpatasvir appears to be a candidate agent worthy of further investigation.
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Integrated Multi-Omics and Spatial Transcriptomics Reveal GUK1 as a Prognostic Biomarker Regulated by the TP53-HSF1 Axis in Breast Cancer.
Background: Guanylate kinase 1 (GUK1) is crucial for nucleotide metabolism, yet its impact on breast cancer (BC) progression remains poorly defined. The objective of the present study is to investigate GUK1 as a prognostic biomarker and therapeutic target. Methods: We employed a multi-omics approach integrating The Cancer Genome Atlas (TCGA) data, machine learning algorithm, High-Definition spatial transcriptomics (Visium HD), single-cell profiling, molecular docking and experimental validation including in vitro knockdown models and Surface Plasmon Resonance (SPR). Results: LASSO regression identified GUK1 as a key metabolic driver. High expression correlated significantly with poor survival and was most pronounced in Human Epidermal Growth Factor Receptor 2 (HER2)-positive and triple-negative subtypes. Spatial transcriptomics revealed GUK1 strongly colocalizes with expanding cancer cell nests, intensifying with disease stage. Single-cell analysis linked GUK1 overexpression to an immunosuppressive microenvironment enriched in exhausted T-cells. Clinically and molecularly, TP53 mutations are highly associated with HSF1 promoter hypomethylation and subsequent HSF1-mediated GUK1 upregulation. We experimentally confirmed this axis, showing that HSF1 or GUK1 knockdown significantly impaired cell migration and suppressed mTOR signaling. Furthermore, while high GUK1 levels predicted resistance to CDK4/6 inhibitors, they enhanced sensitivity to the PI3K/mTOR inhibitor Apitolisib. This therapeutic vulnerability was validated by SPR, which confirmed high-affinity binding between GUK1 and Apitolisib, and by cell viability assays where GUK1 depletion induced drug resistance. Conclusion: GUK1 serves as a robust prognostic biomarker regulated by the TP53-HSF1 axis. Its distinct spatial patterns, immune-suppressive associations, and experimentally validated role in modulating PI3K/mTOR inhibitor sensitivity position GUK1 as a promising target for precision oncology in invasive BC.
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Spatiotemporal dynamics of the cardioimmune niche during lesion repair.
The heart is one of the least regenerative organs in humans, and ischemic heart disease is the leading cause of death worldwide. Understanding the cellular and molecular processes that occur during cardiac wound healing is an essential prerequisite to reducing health burden and improving cardiac function after myocardial tissue damage. Here, by integrating single-cell RNA sequencing with high-resolution spatial transcriptomics, we reconstruct the spatiotemporal dynamics of the fibrotic niches after cardiac injury in adult mice. We reveal a complex multicellular network that regulates cardiac repair, including fibroblast proliferation silencing by Trem2high macrophages to prevent excessive fibrosis. We further discovered a rare population of progenitor-like cardiomyocytes after lesion, promoted by myeloid and lymphoid niche signals. Culturing non-regenerative mouse cardiomyocytes or human heart tissue with these niche factors reactivated progenitor gene expression and cell cycle activity. In summary, this spatiotemporal atlas provides valuable insights into the heterocellular interactions that control cardiac repair.
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The tumor-associated fibroblasts regulate urothelial carcinoma progression.
Tumor-associated fibroblasts (CAFs) regulate tumorigenesis, tumor cell proliferation, and metastasis via secreting related regulatory factors; however, the role of CAFs in regulating the development of upper tract urothelial carcinoma (UTUC) remains unclear. Here, by utilizing single-cell RNA sequencing, single-nucleus RNA sequencing, SpaTial enhanced resolution omics-sequencing, and UTUC immunofluorescence chip cohort to construct the first comprehensive microenvironmental atlas of CAFs, we investigated the roles of CAFs in UTUC progression. Through hierarchical clustering and the copy number variation scores of UTUC epithelial cells, we classified tumor epithelial cells into high-malignant, medium-malignant, and low-malignant potential categories. We found pronounced interaction signals between different CAF subclusters and all three types of epithelial cells, among which high-malignant epithelial cells exhibited the most significant communication signals with the myofibroblastic CAFs1 (myCAFs1) and myCAFs2 subclusters, and FN1 and COL1A1 generated by CAFs played critical roles in this process, suggesting that the progression of UTUC may be attributed to the activation of tumor cells by CAFs. Additionally, both myCAFs1 and myCAFs2 simultaneously affect bladder urothelial carcinoma (BUC) prognosis, with the risk model showing good consistency across cohorts. Therefore, this study constructs a multi-omics landscape of UTUC and identifies common prognostic markers shared with BUC.
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Deciphering potential molecular mechanisms in clear cell renal cell carcinoma based on the ubiquitin-conjugating enzyme E2 related genes: Identifying UBE2C correlates to infiltration of regulatory T cells.
Renal clear cell carcinoma (ccRCC) is a highly aggressive and common form of kidney cancer, with limited treatment options for advanced stages. Recent studies have highlighted the importance of the ubiquitin-proteasome system in tumor progression, particularly the role of ubiquitin-conjugating enzyme E2 (UBE2) family members. However, the prognostic significance of UBE2-related genes (UBE2RGs) in ccRCC remains unclear. In this study, bulk RNA-sequencing and single-cell RNA-sequencing data from ccRCC patients were retrieved from the Cancer Genome Atlas and Gene Expression Omnibus databases. Differential expression analysis was performed to identify UBE2RGs associated with ccRCC. A combination of 10 machine learning methods was applied to develop an optimal prognostic model, and its predictive performance was evaluated using area under the curve (AUC) values for 1-, 3-, and 5-year overall survival (OS) in both training and validation cohorts. Functional enrichment analyses of gene ontology and Kyoto Encyclopedia of Genes and Genomes were conducted to explore the biological pathways involved. Correlation analysis was conducted to investigate the association between the risk score and tumor mutational burden (TMB) and immune cell infiltration. Immunotherapy and chemotherapy sensitivity were assessed by immunophenoscore and tumor immune, dysfunction, and exclusion scores to identify potential predictive significance. In vitro, knockdown of the key gene UBE2C in 786-O cells by specific small interfering RNA to validate its impact on apoptosis, migration, cell cycle, migration, invasion of tumor cells, and induction of regulatory T cells (Tregs). Analysis of sc-RNA revealed that UBE2 activity was significantly upregulated in malignant cells, suggesting its role in tumor progression. A three-gene prognostic model comprising UBE2C, UBE2D3, and UBE2T was constructed by Lasoo Cox regression and demonstrated robust predictive accuracy, with AUC values of 0.745, 0.766, and 0.771 for 1-, 3-, and 5-year survival, respectively. The model was validated as an independent prognostic factor in ccRCC. Patients in the high-risk group had a worse prognosis, higher TMB scores, and low responsiveness to immunotherapy. Additionally, immune infiltration and chemotherapy sensitivity analyses revealed that UBE2RGs are associated with various immune cells and drugs, suggesting that UBE2RGs could be a potential therapeutic target for ccRCC. In vitro experiments confirmed that the reduction of UBE2C led to an increase in apoptosis rate, as well as a decrease in tumor cell invasion and metastasis abilities. Additionally, si-UBE2C cells reduced the release of the cytokine Transforming Growth Factor-beta 1 (TGF-β1), leading to a decreased ratio of Tregs in the co-culture system. This study presents a novel three-gene prognostic model based on UBE2RGs that demonstrates significant predictive value for OS, immunotherapy, and chemotherapy in ccRCC patients. The findings underscore the potential of UBE2 family members as biomarkers and therapeutic targets in ccRCC, warranting further investigation in prospective clinical trials.
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Stalled oligodendrocyte differentiation in IDH-mutant gliomas.
BACKGROUND: Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized. METHODS: Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers. RESULTS: Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas. CONCLUSIONS: Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.
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A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.
Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.
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SLC28A1 inhibits clear cell renal cell carcinoma progression by affecting arachidonic acid metabolism: A novel nucleoside transporter-based targeted therapy strategy.
Clear cell renal cell carcinoma (ccRCC) is a significant clinical challenge due to its heterogeneous nature and variable prognosis. This study aimed to evaluate the prognostic role of nucleoside transporters (NTs) in ccRCC, elucidate the mechanisms underlying the key NT in tumor progression, and develop a targeted therapeutic strategy. Utilizing the Cancer Genome Atlas (TCGA) database, Lasso regression analysis was used for identifying NTs that significantly influenced ccRCC prognosis, which were subsequently used for constructing a risk scoring model. Furthermore, other clinicopathological risk factors were combined to construct a prognostic nomogram incorporating the risk scoring model. Univariate and multivariate Cox regression analyses revealed SLC28A1 as a key NT, and its expression was validated through bioinformatics tools, single-cell sequencing, and cellular/tissue assays. Functional assessments via knockdown and overexpression experiments indicated the role of SLC28A1 in inhibiting proliferation, migration, and invasion of ccRCC cells. In addition, its expression was affected by reactive oxygen species (ROS) and involved in arachidonic acid (AA) metabolism through regulating PLA2G12A via the MAPK signaling pathway, to promote ferroptosis. Moreover, sensitive small molecule drugs binding to SLC28A1 were screened using the Cmap database, which identified sapitinib with therapeutic potential. The efficacy of sapitinib was further enhanced through targeted nanoparticle delivery, significantly inhibiting tumor growth in both in vitro and in vivo models while ensuring biosafety. In conclusion, this research elucidates the mechanism by which SLC28A1 exerts its inhibitory effect in ccRCC and proposes a promising targeted nanotherapeutic approach, offering new insights and strategies for the management of ccRCC.
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Immune dysregulation triggered by inflammatory cytokines in patients with severe respiratory infections.
BACKGROUND: Severe respiratory infections have imposed an immense burden on healthcare worldwide, which could lead to fatal outcomes. The dysfunctional immune response impacts disease severity of respiratory infections, yet its underlying mechanisms remain largely obscure. METHODS: We explored the immunologic response underpinning severe respiratory viral infections by performing single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from 17 patients with coronavirus disease 2019 (COVID-19), including moderate, severe, critical, and convalescent cases. Furthermore, we analyzed the host responses following low- or high-dose vaccination with recombinant protein. RESULTS: We constructed an immunocyte landscape with 299,527 PBMCs. The significant dysregulation of immune homeostasis in severe respiratory viral infections was characterized by an increased ratio of CD14+ monocytes and exhausted CD8+ T cells, and reduced Tregs, memory T cells and cDC2 cells. Notably, highly inflamed CD14+ monocytes overexpressing interleukin (IL)-related genes emerged as central contributor of inflammatory storms in critical patients. Enhanced inflammatory response in exhausted CD8+ T cells, FOS/JUN overexpression in Tregs and Th17 cells, as well as suppressed antigen presentation activity in cDC2 cells were also remarkable features of severe and critical cases. Moreover, the high-dose vaccination with recombinant protein inhibited the inflammatory response of CD14+ monocytes, while enriched the memory T/NK cells to boost protective immunity. In mechanism, activated IL-6-JAK-STAT in CD14+ monocytes and T cells, coupled with impaired interferon (IFN)-α pathway, could drive excessive inflammatory response. CONCLUSIONS: Our study creates a high-resolution transcriptomic atlas that uncovers distinct immune signatures across the disease severity of respiratory infections, which provides valuable resource for mechanistic exploration and therapeutic strategies development. Furthermore, we demonstrate that high-dose recombinant protein vaccines might mitigate the severity of illness. TRIAL REGISTRATION: This study was prospectively registered at ChiCTR (Registration number: ChiCTR2300067787).
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Cryptic fate priming and lineage stabilization during Arabidopsis anther development.
Plant germ cells are specified de novo from somatic tissues, yet how early anther progenitors initiate divergent germline and somatic fates remains unclear. Here, we generated a high-resolution single-cell transcriptomic atlas of Arabidopsis anther development, profiling 66,864 cells from early lineage specification through pollen maturation. We resolved major anther cell types and identified an early L2-derived intermediate population, termed the archesporial-derived state, marked by REM22, ER/ERL1/2, SPL/NZZ, and BAM1. Although classical anatomical studies define archesporial cells, primary sporogenous cells, primary parietal cells, and secondary parietal derivatives based on developmental position and inferred lineage relationships, our analysis showed that these early L2-derived intermediates remain globally similar, forming a shared progenitor-like transcriptional state before lineage stabilization. Trajectory reconstruction, RNA velocity, and module analyses revealed that germline and somatic trajectories first emerge through restricted branch-biased transcriptional programs, which are later amplified into robust lineage-specific identities. Mutant single-cell analyses defined 2 regulatory steps: SPL/NZZ establishes early branch-associated transcriptional programs within the archesporial-derived state, whereas EMS1 stabilizes the somatic/tapetal trajectory and restricts inappropriate enrichment of germline-associated states. Lineage-resolved analyses further defined maturation programs in germline, tapetum, middle layer, and endothecium cells, and identified LBD transcription factors required for normal pollen development. Together, our study reveals a cryptic mode of anther fate priming in which shared early L2-derived intermediates progressively transform limited branch-biased transcriptional programs into distinct reproductive and somatic cell identities through SPL-dependent priming and EMS1-dependent somatic/tapetal stabilization.