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Single-Cell Transcriptomic Analysis Reveals Multicellular Coordination and Signaling Rewiring During Fetal Goat Skeletal Muscle Development.
Fetal skeletal muscle development involves coordinated interactions among myogenic, stromal, vascular, and immune compartments, yet the cellular and molecular programs guiding tissue maturation remain incompletely understood. To address this, we generated a high-resolution single-cell atlas of fetal female goat skeletal muscle and performed trajectory analysis, transcription factor activity profiling, and intercellular communication mapping. Unsupervised clustering identified RUNX2 mesenchymal progenitors, fibro-adipogenic progenitors (FAPs), myofibroblasts, endothelial cells, macrophages, differentiating myocytes, and mature skeletal muscle fibers, revealing a heterogeneous ecosystem in which stromal populations support myogenic progression and vascular and immune cells contribute to tissue organization. Pseudotime analysis traced a maturation continuum from differentiation-competent myocytes to contractile fibers, marked by sequential activation of extracellular matrix remodeling, cytoskeletal stabilization, and sarcomere assembly. KEGG and GO enrichment highlighted stage-specific engagement of ErbB, Hedgehog, and Hippo signaling, as well as cell cycle and ubiquitin-mediated proteolysis pathways, linking proliferation, differentiation, and structural maturation. Transcription factor profiling revealed early-stage proliferative and morphogenetically permissive states driven by E2F4/5, HMGA2, and HAND2, transitioning to late-stage differentiation, ECM remodeling, and tissue stabilization orchestrated by CEBPB, CREB3L1, ELK1, and E2F2. Cell-cell communication analysis showed a developmental redistribution of signaling authority, from ECM-driven, progenitor-centered networks to modular, structurally stabilized interactions. These findings define the cellular, transcriptional, and signaling framework orchestrating fetal skeletal muscle maturation.
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Actin-like Protein 6A Expression Correlates with Cancer Stem Cell-like Features and Poor Prognosis in Ovarian Cancer.
Ovarian cancer has the highest mortality rate among gynecological cancers, often diagnosed at the late stage and lacking an effective targeted therapy. Although the study of malignant features of cancer, considered to be cancer stem cells (CSCs), is emerging, the aim of this study was to predict and explore the possible mechanism and clinical value of genetic markers in the development of ovarian cancer from a combined database with CSCs features. The common differentially expressed genes (DEGs) were selected in GSE185833 and GSE176246 datasets from the Gene Expression Omnibus (GEO). The GSE185833 dataset was created to reveal gene expression profiles of peritoneal metastasis tissues using single-cell sequencing, and the GSE176246 dataset was determined from gene expression profiles of chemotherapy-refractory ovarian cancer cell lines compared with ovarian cancer cell lines by RNA-seq analysis. By analyzing the correlation between common DEGs and prognosis of ovarian cancer and its possible pathways and functions were predicted by The Cancer Genome Atlas (TCGA) database. The expression levels of 11 genetic markers were significantly elevated in highly invasive and chemoresistant ovarian cancer. The expression of Actin-like protein 6A (ACTL6A) was found to be correlated with survival prognosis, and the total survival time of the patients with high expression of ACTL6A was shorter than those with low expression. Gene set enrichment analysis (GSEA) showed that ACTL6A positively enriched the gene set of 'Cell cycle' and ACTL6A negatively enriched the gene set of focal adhesion. CP724714, a human epidermal growth factor receptor 2 (HER2) inhibitor, could serve as a therapeutic option when ACTL6A levels are high in ovarian cancer cells. The high expression of ACTL6A is a poor prognostic factor in ovarian cancer and may serve as an effective biomarker for predicting treatment-refractory, metastasis, and prognosis of patients with ovarian cancer. The use of HER2 inhibitors is a promising therapeutic strategy against chemoresistant ovarian cancer.
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Role of TAP1 in the identification of immune-hot tumor microenvironment and its prognostic significance for immunotherapeutic efficacy in gastric carcinoma.
BACKGROUND: Gastric cancer (GC), a multifaceted gastrointestinal malignancy, is the fourth most prevalent contributor to cancer-related fatalities globally. As a member of the ATP-binding cassette (ABC) family, transporter associated with antigen processing 1 (TAP1) is crucial for conveying antigen peptides from the cytoplasm to the lumen of the endoplasmic reticulum and subsequently loading them onto the major histocompatibility complex (MHC) class I molecules. Recent studies have established the biological significance of TAP1 in upholding tumor survival and facilitating immune evasion by remodeling the tumor microenvironment (TME) and orchestrating immune infiltration. The study was conducted to elucidate the association of TAP1 expression with immunological characteristics, and sought to exploit the value of TAP1 as a biomarker reflecting the inflamed TME and immunotherapeutic response. METHODS: RNA-sequencing profiles and clinical annotations were obtained from The Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD) cohort and Gene Expression Omnibus (GEO) portal. Preprocessing was conducting using the limma package. Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules and TAP1 co-expressed genes (CEGs) based on correlation patterns. Consensus clustering and silhouette analysis determined the optimal number of TAP1-related groups. Gene expression profiles were integrated and classified using the pamr package. The Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) algorithm and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate immunological characteristics. Differential expression analysis was conducted using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Single-cell RNA sequencing (scRNA-seq) datasets were analyzed using the Seurat toolkit to characterize cell types. RESULTS: Within this investigation, no significant differences in TAP1 expression were observed among patients exhibiting various clinicopathological features, indicating that TAP1 expression was not specific to molecular subtypes. Subsequent analysis revealed a positive correlation between TAP1 and diverse immunological traits, encompassing immunomodulators, tumor-infiltrating immune cells, as well as immune checkpoints across multiple datasets. Besides, within a GC immunotherapy cohort, individuals displaying high TAP1 expression demonstrated an increased likelihood of achieving complete remission (CR) post-treatment, suggesting heightened sensitivity to immunotherapy. In the clinical cohort, TAP1 overexpression in GC patients was positively correlated with CD8. CONCLUSIONS: TAP1 appears linked to an inflamed TME and serves as a prospective biomarker for discerning immunological attributes and gauging immunotherapeutic responses in GC, particularly in identifying immune-reactive tumors.
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A Single-Cell Transcriptome Atlas Characterizes the Immune Landscape of Human Testes During Aging.
Aging disrupts immune regulation, affecting tissue function and increasing vulnerability to various diseases. However, the effects of aging on immune cells within human testes are not well understood. In this study, we utilized single-cell RNA sequencing to profile immune cells from 33 human testis samples from individuals aged 21 to 69. Our analysis revealed key immune cell types, including CD8+ T cells, monocytes, cDC2 cells, and various macrophage subtypes within the testes. We observed an age-related change in monocytes and MRC1hi tissue-resident macrophage (TRM), a pattern consistent in both human and mouse testes. Individuals aged 40 and older showed notable shifts in pathways related to phagocytosis, cytokine signaling, and antigen presentation. Monocytes also exhibited pro-inflammatory characteristics, potentially contributing to the low-grade inflammation commonly associated with aging. Together, these findings provide insights into age-related immune cell alterations in human testes and uncover molecular mechanisms underlying these shifts, offering a valuable resource for understanding immune aging in the reproductive system.
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Identification and verification of SPP1 in anoikis as a prognostic biomarker for intestinal metaplasia and gastric cancer.
Anoikis is a form of apoptosis induced by cell detachment from the extracellular matrix, and cancer cells must evade it to metastasize. Gastric cancer (GC) remains a leading global cause of cancer-related mortality, with intestinal metaplasia (IM) established as a key premalignant lesion. This study explored the multi-omics features of the anoikis-related gene SPP1 across the control-IM-GC cascade, focusing on its links to immunity and prognosis. Comprehensive transcriptome analyses were conducted using datasets from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and the GeneCards database via the R programming language. By integrating Weighted Gene Co-expression Network Analysis (WGCNA) and competing endogenous RNA (ceRNA) networks, alongside Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), the study explored the immunological roles of Secreted Phosphoprotein 1 (SPP1) in GC. Furthermore, immune infiltration and immune checkpoint analyses were combined with single-cell RNA sequencing (scRNA-seq) to elucidate the tumor microenvironment. Finally, Cox proportional hazards regression and Receiver Operating Characteristic (ROC) curve analyses were utilized to assess the prognostic significance of SPP1 and to construct a predictive risk signature. RT-qPCR/Western blot (32 human tissues) and in vitro assays were conducted to validate SPP1's expression and function. SPP1 was significantly upregulated across the Correa cascade, with high predictive accuracy, and was associated with survival and potential immunotherapy relevance. Higher levels were associated with a poorer prognosis. In vitro, SPP1 inhibition reduced GC cell migration, enhanced apoptosis, and induced S/G2 phase arrest. To our knowledge, this is the first study to associate SPP1 with IM/GC. Our findings suggest that it may serve as a prognostic biomarker, with immunotherapeutic implications that require further study.
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Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies.
Diabetic kidney disease (DKD) occurs in ∼40% of patients with diabetes and causes kidney failure, cardiovascular disease, and premature death. We analyzed the response of a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas of ∼1 million cells revealed a heterogeneous response of all kidney cell types both to DKD and its treatment. Both monotherapy and combination therapies targeted differing cell types and induced distinct and non-overlapping transcriptional changes. The early effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the S1 segment of the proximal tubule suggest that this drug class induces fasting mimicry and hypoxia responses. Diabetes downregulated the spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubule that was specifically rescued by SGLT2i. In vitro proximal tubule knockdown of Srsf7 induced a pro-inflammatory phenotype, implicating alternative splicing as a driver of DKD and suggesting SGLT2i regulation of proximal tubule alternative splicing as a potential mechanism of action for this drug class.
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Integrated analysis identifies a palmitoylation-associated prognostic model (ACSM5/SKA3) for lung adenocarcinoma across multiple cohorts.
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains associated with poor prognosis despite therapeutic advances. Protein palmitoylation, particularly reversible S-palmitoylation, modulates oncogenic signaling, membrane localization, and immune checkpoint stability, but the prognostic landscape of palmitoylation-related genes (PRGs) in LUAD and their relationship with the tumor microenvironment are not well defined. METHODS: PRGs were curated from GeneCards and integrated with transcriptomic and clinical data from The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) cohort. Differential expression and univariate Cox analyses were performed to identify prognostic PRGs, which were then used for consensus clustering to define molecular subtypes and to construct a LASSO-Cox prognostic model. Associations between the risk score and functional pathways, genomic alterations, tumor mutational burden (TMB), tumor immune dysfunction and exclusion (TIDE) scores, and immune infiltration were evaluated. Three Gene Expression Omnibus (GEO) cohorts were used for external validation. Single-cell RNA sequencing (scRNA-seq) datasets and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) of paired LUAD and adjacent tissues were used to assess cell type-associated expression and validate key genes. RESULTS: We identified 201 differentially expressed PRGs in LUAD and 15 genes significantly associated with overall survival, including the protective gene ACSM5 and the risk gene SKA3. PRG-based consensus clustering defined two molecular subtypes with distinct prognoses, differential enrichment of metabolism- versus proliferation-related pathways, and divergent immune microenvironment features. A two-gene signature comprising ACSM5 and SKA3 stratified patients into high- and low-risk groups in The Cancer Genome Atlas (TCGA) and three external cohorts, with time-dependent area under the curve (AUCs) of 0.717, 0.733, and 0.697 at 1, 3, and 5 years in TCGA and comparable performance in GEO validation cohorts (5-year AUC up to 0.778), indicating moderate discriminative performance. Low-risk patients generally showed higher stromal and immune scores and increased infiltration of multiple immune cell subsets, along with complex patterns in TMB and TIDE indices. Single-cell analyses indicated predominant expression of ACSM5 in macrophages and of SKA3 in proliferating CD8+ T cells and macrophages, and RT-qPCR confirmed downregulation of ACSM5 and upregulation of SKA3 in LUAD tissues. CONCLUSION: This integrated analysis outlines a palmitoylation-associated molecular framework in LUAD and supports an ACSM5/SKA3 two-gene signature as a candidate prognostic tool that stratifies patient outcomes and reflects distinct metabolic, proliferative, and immune microenvironmental states, potentially providing a palmitoylation-associated basis for risk stratification and for the design of future mechanistic and therapeutic studies in LUAD.
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Desmoglein-1 coordinates cell proliferation and actin dynamics to promote epidermal morphogenesis.
Skin development depends on coordinated biochemical and mechanical signaling to form a multilayered epidermal barrier. Our previous work demonstrated that the stratified tissue-specific desmosomal cadherin Desmoglein-1 (Dsg1) promotes epidermal differentiation in human in vitro models. Dsg1 first appears in the developing mouse epidermis around E14, coinciding with a developmental transition in stratification and the onset of terminal differentiation, raising the question of how Dsg1 contributes to epidermal morphogenesis in vivo . We generated a wild-type (WT) single-cell RNA sequencing (scRNA-seq) atlas of murine skin and integrated scRNA-seq data from Dsg1 knockout (Dsg1 KO) embryos spanning E14.5, E15.5, E16.5, and E18.5. Six keratinocyte subpopulations were annotated, including a Transitional subpopulation co-expressing basal and suprabasal markers, positioned between basal and differentiated states. Dsg1 KO epidermis exhibited reduced thickness at E14.5-E15.5, but recovered by E16.5-E18.5, suggesting compensatory adaptation. Differential gene expression analysis revealed enrichment of cell-cycle and actin-associated programs in Dsg1 KO during late development. EdU incorporation and PCNA staining confirmed increased proliferation in superficial layers accompanied by altered actin organization and changed cell morphology. Notably, actin and the Arp2/3 actin nucleation-promoting factor N-WASP exhibited marked changes in distribution during early and late development, respectively. Mechanistically, Dsg1 associates with Nck1, an adaptor linking N-WASP to Arp2/3-dependent actin polymerization. Silencing Nck1 or N-WASP reduced Dsg1-mediated stratification significantly, while a Nck1-binding-deficient Dsg1 mutant failed to rescue stratification in Dsg1-deficient keratinocytes in vitro . Together, these findings identify a Dsg1-Nck1-N-WASP axis linking desmosomal adhesion to cytoskeletal remodeling and support a model in which Dsg1 coordinates cell-cycle, cell morphology, and actin dynamics to drive epidermal morphogenesis.
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RETRACTED: Exploring the tumor microenvironment: Chemokine-related genes and immunotherapy/chemotherapy response in clear-cell renal cell carcinoma.
BACKGROUND: The treatment of clear-cell renal cell carcinoma (ccRCC) remains challenge. Chemokines laid impact on the proliferation and metastasis of cancer cells. The objective was to identify the chemokine-related genes and construct a prognostic model for ccRCC. METHODS: Bulk transcriptomic data (n = 531), single-cell RNA sequencing (scRNA-seq) dataset GSE159115, and other validation cohorts were acquired from the Cancer Genome Atlas Program (TCGA) and GEO databases. All clustering analysis was conducted by Seurat R package. Gene set enrichment analysis (GSEA), immune infiltration analysis, single nucleotide variations (SNV) analysis, and predictive response analysis of immunotherapy/chemotherapy were conducted. 786-O and A498 cell lines were cultured and applied into CCK-8, Western blot, and RT-qPCR kits. RESULTS: Univariate Cox analysis was used to screen out chemokine-related genes related to survival. ZIC2, SMIM24, COL7A1, IGF2BP3, ITPKA, ADAMTS14, CYP3A7, and AURKB were identified and applied for the construction of the prognostic model. High-risk group had a poorer prognosis than the low-risk group in each dataset. Memory CD8+ T cells, macrophages, and memory B cells were higher in the high-risk group, while the content of basophils was higher in the low-risk group. Bortezomib_1191, Dactinomycin_1911, Docetaxel_1007, and Daporinad_1248 were more sensitive to high-risk groups than low-risk groups. Moreover, we found that IGF2BP3 significantly elevated in both 786-O and A498 cell lines resistance to sunitinib. Knockdown of IGF2BP3 markedly reduced ccRCC cell migration and viability. CONCLUSION: Our study has yielded a novel prognostic model of chemokine-related genes based on comprehensive transcriptional atlas of ccRCC patients, shedding light on the significant impact of the tumor microenvironment on biology and immunotherapy response of ccRCC. We identified IGF2BP3 as a pivotal regulator in regulating ccRCC resistance to sunitinib.
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3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) is a potential diagnostic and prognostic biomarker in colon adenocarcinoma.
Colon cancer represents a global health challenge. The 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase 2 (PAPSS2) is the key enzyme to generate PAPS, which is the universal sulfonate donor for all sulfation reactions. However, the correlation between PAPSS2 and diagnosis, prognosis, and immune cell infiltration in colon adenocarcinoma (COAD) has rarely been mentioned. We analyzed PAPSS2 expression levels in pan-cancer from The Cancer Genome Atlas (TCGA) database; and validated it in the Gene Expression Omnibus (GEO) database. RNA-seq data were analyzed using the R package to identify differentially expressed genes (DEGs) between COAD tissues with high and low PAPSS2 expression from multiple databases. The ssGSEA algorithm was used to analyze the correlation between PAPSS2 and immune cell infiltration in COAD. Tumor tissues and normal tissues were classified and assayed at the single-cell level to analyze differences in PAPSS2 expression. CCK8 and EdU assays were used to validate proliferative capacity; wound healing assays to validate migratory capacity; and Transwell assays to examine changes in invasive capacity. The PAPSS2 expression level was significantly lower in the tumor tissues and associated with worse clinical parameters and prognosis in COAD patients. And we constructed a transcriptional regulatory network involving FLI1 and hsa-miR-152-3p targeting PAPSS2 to support the role of PAPSS2.Enrichment analysis revealed that PAPSS2 is involved in O-glycan biosynthesis, TP53 pathway and extracellular matrix formation. PAPSS2 was found to be positively associated with the infiltration of numerous immune cells, immunomodulatory factors and chemokines. Cytological experiments demonstrated that PAPSS2 knockdown enhanced the proliferation, migration, and invasion of HCT116 and HT-29 cells. Our study suggests that PAPSS2 acts as a promising diagnostic and prognostic biomarker, which facilitates malignant progression in part through its regulation of the p53 signaling pathway.