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Spatial compartmentalization of melanoma cell states reveals CAF-associated tumor cells with enhanced proliferative capacity.
BACKGROUND: Cancer-associated fibroblasts (CAFs) are key components of the melanoma tumor microenvironment and have been implicated in immune evasion and therapy resistance. However, the spatial relationships between CAFs, extracellular matrix (ECM) remodeling, and immune exclusion remain incompletely characterized. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics from primary melanoma samples (892 regions of interest) to investigate the landscape of CAF-immune interactions. CAF scores were calculated based on five fibroblast-associated genes. Differential expression analysis, Spearman correlation, and cell state subclustering were performed to characterize the spatial organization of the tumor microenvironment. Findings were examined using TCGA bulk RNA-seq data and drug sensitivity was assessed using the GDSC database. RESULTS: CAF-high regions exhibited significantly lower immune scores compared to CAF-low regions (ρ = -0.442, p < 0.001), with enrichment of ECM-related genes (COL1A1, COL1A2, DCN, FBLN1) and downregulation of immune genes (PTPRC, CD4, CD8A). Spatial co-expression of FN1 and its integrin receptor subunit ITGB1 was observed (ρ = 0.100, p = 0.003), supporting a potential role for ECM-receptor signaling in immune exclusion. Six distinct melanoma cell states were identified, with CAF-associated tumor states (State 4) exhibiting significantly higher proliferative capacity than immune-associated states (State 5) (p = 0.007). The CAF signature correlated with cisplatin sensitivity (ρ = -0.627, p < 0.001) and trametinib resistance (ρ = 0.354, p = 0.009). CONCLUSIONS: This study provides a spatial atlas of CAF-immune interactions in melanoma. CAF abundance is negatively correlated with immune infiltration at the spatial level, with ECM remodeling and FN1-ITGB1 signaling potentially mediating this immune exclusion. The CAF signature showed correlations with drug sensitivity in cell line models, warranting further investigation in CAF-containing systems.
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Single-cell RNA-seq reveals heterogeneity in hiPSC-derived muscle progenitors and E2F family as a key regulator of proliferation.
Human pluripotent stem cell-derived muscle progenitor cells (hiPSC-MuPCs) resemble fetal-stage muscle progenitor cells and possess in vivo regeneration capacity. However, the heterogeneity of hiPSC-MuPCs is unknown, which could impact the regenerative potential of these cells. Here, we established an hiPSC-MuPC atlas by performing single-cell RNA sequencing of hiPSC-MuPC cultures. Bioinformatic analysis revealed four cell clusters for hiPSC-MuPCs: myocytes, committed, cycling, and noncycling progenitors Using FGFR4 as a marker for noncycling progenitors and cycling cells and CD36 as a marker for committed and myocyte cells, we found that FGFR4+ cells possess a higher regenerative capacity than CD36+ cells. We also identified the family of E2F transcription factors are key regulators of hiPSC-MuPC proliferation. Our study provides insights on the purification of hiPSC-MuPCs with higher regenerative potential and increases the understanding of the transcriptional regulation of hiPSC-MuPCs.
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Targeting CLIC6 with theaflavin enhances radiotherapy sensitivity in ER+/HER2- breast cancer.
BACKGROUND: Radiotherapy is a cornerstone of breast cancer treatment; however, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) tumors frequently exhibit intrinsic radioresistance. Understanding the molecular mechanisms underlying this resistance is crucial for improving therapeutic outcomes. This study aims to identify key molecular determinants of intrinsic radioresistance in ER+/HER2- breast cancer and to explore potential radiosensitization strategies targeting these determinants. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) data from ER+/HER2- breast tumors before and after radiotherapy with transcriptomic profiles from The Cancer Genome Atlas (TCGA). A high-dimensional weighted gene co-expression network analysis (hdWGCNA) was employed to identify gene modules associated with clinical traits. Functional assays were conducted in ER+ breast cancer cells with chloride intracellular channel 6 (CLIC6) overexpression or knockdown. A molecular docking analysis revealed that theaflavin specifically interacts with CLIC6. Further, clonogenic assays and Cell Counting Kit-8 (CCK-8) proliferation assays were performed to validate the biological effects of theaflavin and CLIC6 following radiotherapy. RESULTS: The hdWGCNA identified a luminal A-like gene module correlated with progesterone receptor (PR) positivity and low Ki67 expression, within which CLIC6 emerged as a key hub gene. Elevated CLIC6 expression enhanced radioresistance, whereas CLIC6 knockdown increased radiosensitivity. Molecular docking confirmed that theaflavin binds to CLIC6 with high affinity (binding energy -8.8 kcal/mol). Theaflavin treatment significantly enhanced radiosensitivity in wild-type and CLIC6-overexpressing cells but had no effect in CLIC6-knockdown or ER-negative (ER-) cells. CONCLUSIONS: This study identified CLIC6 as a novel gene associated with radioresistance in ER+/HER2- breast cancer and showed that theaflavin functions as a natural radiosensitizer in a CLIC6-dependent manner, consistent with its high-affinity interaction with CLIC6. Targeting CLIC6 may provide a promising strategy to enhance radiotherapy efficacy in this common breast cancer subtype.
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Yang-Xue-An-Tai Decoction Treats URSA by regulating the differentiation of proliferating decidual stromal cells through multiple targets.
ETHNOPHARMACOLOGICAL RELEVANCE: Unexplained recurrent spontaneous abortion (URSA) accounts for approximately 50% of all recurrent spontaneous abortion cases, severely endangering the physical and mental health of women of childbearing age. Yang-Xue-An-Tai Decoction (YXAT), a traditional Chinese medicine (TCM) in-hospital preparation, has been clinically effective and safe for URSA treatment for over 30 years, but its underlying mechanism remains unclear. AIM OF THE STUDY: The purpose of this study was to explore the pharmacological mechanism of YXAT in the treatment of URSA, focusing on clarifying its multi-target mechanism in regulating the differentiation of decidual stromal cell (DSC) subtypes. MATERIALS AND METHODS: The classic Clark mouse model of URSA was established to verify YXAT's improvement effect on abortion. Single-cell RNA sequencing (scRNA-seq) was employed to construct the uterine single-cell atlas of model and YXAT-treated mice at gestational day 7.5 (GD7.5). YXAT's regulation on decidualization was verified by detecting decidualization markers; decidual stromal cell subtypes were analyzed, and its regulatory effect on subtype differentiation was confirmed via pseudotime analysis and intercellular communication. Moreover, YXAT's role in regulating abnormal decidual stromal cell differentiation in URSA was validated in animal and clinical samples. RESULTS: YXAT significantly improved decidualization and improved pregnancy outcomes in URSA mice. Subcluster analysis of DSCs revealed that proliferating DSCs (proDSCs)-a central hub for DSC differentiation-were abnormally downregulated in URSA mice, and this reduction was restored by YXAT, with a significantly better effect than that of the positive drug dydrogesterone. Integrated analysis identified Lgals1 as a key overlapping gene regulated by YXAT and linked to proDSC differentiation. We propose that Lgals1 acts as a candidate regulator, and the recovery of Lgals1 expression coincides with the restoration of proDSC differentiation following YXAT treatment. Additionally, URSA mice exhibited enhanced NK cell-proDSC communication with excessive inflammatory activation (e.g., Spp1-Cd44, Gzma-Pard3) and immune suppression-related ligand-receptor pairs (e.g., Spp1-(Itgav + Itgb5), Lamb2-Dag1), which were attenuated by YXAT. The abnormal downregulation of proDSCs was further verified in human URSA samples, highlighting its clinical relevance. CONCLUSIONS: Disordered proDSC differentiation correlates with defective decidualization and adverse pregnancy phenotypes in URSA mice. Multiple favorable cellular and molecular changes are observed alongside YXAT intervention, including recovered proDSC abundance, restored expression of the differentiation-associated gene Lgals1, and normalized abnormal NK cell-proDSC intercellular signaling. These correlative observations offer new insights into the clinical potential of YXAT and advance our understanding of TCM interventions against URSA.
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Overexpression of TCF7L2 promotes the viability and migration of MHCC-97H human hepatocellular carcinoma cells by upregulating MT-ND4L.
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with high metabolic adaptability. TCF7L2, a transcription factor implicated in type 2 diabetes and cancer, is overexpressed in HCC. However, its specific role in HCC metabolic reprogramming is not well defined. We aimed to elucidate the previously unrecognized molecular mechanisms through which TCF7L2 impacts HCC progression. METHODS: To investigate the function of TCF7L2, a stable MHCC-97H cell line with TCF7L2 overexpression was established via lentiviral transduction. Cell viability and migration were assessed by Cell Counting Kit-8 (CCK-8) and Transwell assays. Transcriptomic profiling [RNA sequencing (RNA-seq)] was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis [Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA)] and bioinformatics promoter analysis (the JASPAR CORE database) were conducted. Clinical correlations, survival analysis, and tumor microenvironment (TME) interrogation were performed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and single-cell datasets [Human Protein Atlas (HPA), CellChat]. Drug sensitivity was predicted via the Genomics of Drug Sensitivity in Cancer (GDSC) database. RESULTS: TCF7L2 overexpression significantly promoted HCC cell proliferation and migration. Transcriptomic analysis revealed that TCF7L2 drives a profound metabolic shift, with key enrichments in lipid homeostasis, fatty acid β-oxidation, and the PI3K/Akt pathway. Mechanistically, TCF7L2 directly binds to the promoter of CPT1A, the rate-limiting enzyme of fatty acid oxidation, and indirectly upregulates the mitochondrial gene MT-ND4Lvia a strong positive correlation with the mitochondrial transcription factor TFAM. In clinical cohorts, TCF7L2 was overexpressed in HCC and its expression correlated positively with MT-ND4L, MKI67, and SNAI1, and served as a predictor of poor overall survival (OS). Furthermore, TCF7L2-high tumors were enriched in hepatic progenitor cell (HPC)-like niches, mediated by enhanced ANGPTL4 signaling. High TCF7L2 expression predicted increased sensitivity to PI3K/mTOR pathway inhibitors. CONCLUSIONS: TCF7L2 acts as a master metabolic regulator in HCC, coordinating lipid catabolism and mitochondrial biogenesis to drive aggressive tumor behavior. It further remodels the TME towards an HPC-like state and predicts sensitivity to metabolic-targeted therapies. These findings identify TCF7L2 as a key prognostic biomarker and a promising therapeutic target.
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PCDH1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy.
BACKGROUND: Pancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds. RESULTS: The RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD. CONCLUSION: PCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.
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Single-cell transcriptomic analysis reveals metabolic reprogramming and tumor microenvironment remodeling in aldosterone-producing adenoma.
Aldosterone-producing adenoma (APA) is a significant cause of primary aldosteronism, however, its cellular heterogeneity remains unclear. We performed single-cell RNA sequencing on adrenal tissues from three APA patients and three controls. We identified CAPS+ zona glomerulosa (ZG)-like cells in APA with upregulated lipogenesis, oxidative phosphorylation, and mTOR signaling, indicating metabolic reprogramming. Pseudotime analysis revealed disrupted differentiation and aberrant CYP11B1, CYP11B2, and SULT2A1 expression. Oncogenic Myc, Wnt, and G2/M pathways were activated in ZR-like clusters. APA showed immune infiltration (B cells, CD8+ T cells, M1 macrophages), angiogenic activation (VWF+ endothelial cells), and fibroblast-driven stromal remodeling via Hedgehog signaling. Our study provides a comprehensive single-cell atlas of APA, uncovering key tumorigenic mechanisms and identifying potential biomarkers (e.g., CAPS, VWF, UPK3B) and therapeutic targets, including mTOR and Hedgehog/Wnt pathways. These findings advance the genomic understanding of adrenal tumors and support precision medicine development.
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COL1A1-positive endothelial cells promote gastric cancer progression via the ANGPTL4-SDC4 axis driven by endothelial-to-mesenchymal transition.
Gastric cancer (GC) is an aggressive and heterogeneous disease with poor survival outcomes. The progression of GC involves complex, multi-step processes. Endothelial cells (ECs) play a crucial role in tumor angiogenesis, proliferation, invasion, and metastasis, particularly through the process of endothelial-to-mesenchymal transition (EndoMT). However, the specific role and mechanisms of EndoMT in gastric cancer remain unclear. Based on 6 GC single-cell RNA-sequencing (scRNA-seq) cohorts (samples = 97), we established an EndoMT-related gene signature, termed EdMTS. Leveraging this gene signature, ssGSEA was applied to calculate sample scores across multiple bulk RNA-seq datasets, which include information on immunotherapy, metastasis, GC progression, and survival. Moreover, we applied the Monocle2 method to calculate cell pseudotime and used CellChat to analyze interactions between malignant and EC cells. We verified the molecular mechanism by multiple immunofluorescence and cell function experiments. Findings In this study, we established a single-cell atlas of ECs in GC and identified a subpopulation of COL1A1+ ECs that play a critical role in tumor progression and metastasis. These COL1A1+ ECs were significantly associated with worse clinical outcomes in GC patients. Further analysis revealed that COL1A1+ ECs originated from lymphatic ECs and underwent EndoMT through the upregulation of CEBPB, driving tumor invasiveness. Moreover, COL1A1+ ECs interacted with malignant cells via ANGPTL4-SDC4 axis, enhancing invasion and migration. These findings provide a deeper understanding of the role of COL1A1+ ECs in GC progression and highlight potential therapeutic targets for disrupting the EndoMT process in these cells to provide a benefit for GC patients.
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Multiomics Analyses Provide New Insight into Genetic Variation of Reproductive Adaptability in Tibetan Sheep.
Domestication and artificial selection during production-oriented breeding have greatly shaped the level of genomic variability in sheep. However, the genetic variation associated with increased reproduction remains elusive. Here, two groups of samples from consecutively monotocous and polytocous sheep were collected for genome-wide association, transcriptomic, proteomic, and metabolomic analyses to explore the genetic variation in fecundity in Tibetan sheep. Genome-wide association study revealed strong associations between BMPR1B (p.Q249R) and litter size, as well as between PAPPA and lambing interval; these findings were validated in 1,130 individuals. Furthermore, we constructed the first single-cell atlas of Tibetan sheep ovary tissues and identified a specific mural granulosa cell subtype with PAPPA-specific expression and differential expression of BMPR1B between the two groups. Bulk RNA-seq indicated that BMPR1B and PAPPA expressions were similar between the two groups of sheep. 3D protein structure prediction and coimmunoprecipitation analysis indicated that mutation and mutually exclusive exons of BMPR1B are the main mechanisms for prolific Tibetan sheep. We propose that PAPPA is a key gene for stimulating ovarian follicular growth and development, and steroidogenesis. Our work reveals the genetic variation in reproductive performance in Tibetan sheep, providing insights and valuable genetic resources for the discovery of genes and regulatory mechanisms that improve reproductive success.
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Integrating network analysis with differential expression to uncover therapeutic and prognostic biomarkers in esophageal squamous cell carcinoma.
Introduction: Esophageal squamous cell carcinoma (ESCC) accounts for over 90% of all esophageal tumors. However, the molecular mechanism underlying ESCC development and prognosis remains unclear, and there are still no effective molecular biomarkers for diagnosing or predicting the clinical outcome of patients with ESCC. Here, we used bioinformatics analysis to identify potential biomarkers and therapeutic targets for ESCC. Methodology: Differentially expressed genes (DEGs) between ESCC and normal esophageal tissue samples were obtained by comprehensively analyzing publicly available RNA-seq datasets from the TCGA and GTEX. Gene Ontology (GO) annotation and Reactome pathway analysis identified the biological roles of the DEGs. Moreover, the Cytoscape 3.10.1 platform and subsidiary tools such as CytoHubba were used to visualize the DEGs' protein-protein interaction (PPI) network and identify hub genes, Furthermore our results are validated by using Single-cell RNA analysis. Results: Identification of 2524 genes exhibiting altered expression enriched in pathways including keratinization, epidermal cell differentiation, G alpha(s) signaling events, and biological process of cell proliferation and division, extracellular matrix (ECM) disassembly, and muscle function. Moreover, upregulation of hallmarks E2F targets, G2M checkpoints, and TNF signaling. CytoHubba revealed 20 hub genes that had a valuable influence on the progression of ESCC in these patients. Among these, the high expression levels of four genes, CDK1 MAD2L1, PLK1, and TOP2A, were associated with critical dependence for cell survival in ESCC cell lines, as indicated by CRISPR dependency scores, gene expression data, and cell line metadata. We also identify the molecules targeting these essential hub genes, among which GSK461364 is a promising inhibitor of PLK1, BMS265246, and Valrubicin inhibitors of CDK1 and TOP2A, respectively. Moreover, we identified that elevated expression of MMP9 is associated with worse overall survival in ESCC patients, which may serve as potential prognostic biomarker or therapeutic target for ESCC. The single-cell RNA analysis showed MMP9 is highly expressed in myeloid, fibroblast, and epithelial cells, but low in T cells, endothelial cells, and B cells. This suggests MMP9's role in tumor progression and matrix remodeling, highlighting its potential as a prognostic marker and therapeutic target. Discussion: Our study identified key hub genes in ESCC, assessing their potential as therapeutic targets and biomarkers through detailed expression and dependency analyses. Notably, MMP9 emerged as a significant prognostic marker with high expression correlating with poor survival, underscoring its potential for targeted therapy. These findings enhance our understanding of ESCC pathogenesis and highlight promising avenues for treatment.