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Decoding innate lymphoid cell heterogeneity and plasticity in colorectal cancer.
BACKGROUND: In colorectal cancer (CRC), innate lymphoid cells (ILCs) play a vital role in preserving and modulating immune homeostasis within the intestinal environment. However, the origins and diverse functions of ILCs in CRC remain poorly understood, making it difficult to clarify how these cells contribute to disease progression and influence therapeutic efficacy. METHODS: Single-cell RNA sequencing (scRNA-seq) generated an atlas of ILCs from multiple tissues (bone marrow, blood, and intestine), revealing their origins, heterogeneity, and plasticity. Spatial transcriptomics (ST) and immunofluorescence (IF) defined their specific cellular neighbourhoods within the tumour microenvironment. In vitro co-culture assays were performed to validate the regulatory role of ILC2s in B cell maturation. Bulk RNA sequencing and flow cytometry were employed to assess the survival and therapeutic response potential of ILCs. RESULTS: Intestinal ILCs have two distinct origins: ILC3-CD83 cells derived from the fetal gut, which persist into adulthood; and ILC2 and ILC3-S100A4 cells that might originate from the bone marrow and migrate through the circulation to colonise intestinal tissues. The tissue-resident ILC3 subsets exhibited diverse functional roles in CRC. Specifically, trajectory analysis showed that ILC3s differentiated into either stress-responsive ILC3-HSPA1B cells or cytotoxic ILC1/NK cells in CRC. Additionally, by using spatial transcriptomics analysis combined with functional assays, we found that bone marrow-derived ILC2s preferentially localise in tertiary lymphoid structures (TLSs), where they likely support B cell maturation. Notably, higher ILC2 abundance correlated with better clinical outcomes and greater therapeutic benefit. CONCLUSIONS: This study reveals the distinct origins and functional heterogeneity of intestinal ILC subsets in CRC. The enrichment of bone marrow-derived ILC2s in TLSs, where they likely support B cell maturation, is associated with improved prognosis and favourable immunotherapy response, which may serve as biomarkers for survival and therapeutic efficacy in CRC.
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Prognostic and therapeutic potential of gene profiles related to tertiary lymphoid structures in colorectal cancer.
The role of tertiary lymphoid structures (TLS) in oncology is gaining interest, particularly in colorectal carcinoma, yet a thorough analysis remains elusive. This study pioneered a novel TLS quantification system for prognostic and therapeutic response prediction in colorectal carcinoma, alongside a comprehensive depiction of the TLS landscape. Utilizing single-cell sequencing, we established a TLS score within the Tumor Immune Microenvironment (TIME). Analysis of tertiary lymphoid structure-related genes (TLSRGs) in 1,184 patients with colon adenocarcinoma/rectum adenocarcinoma (COADREAD) from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases led to the identification of two distinct molecular subtypes. Differentially expressed genes (DEGs) further segregated these patients into gene subtypes. A TLS score was formulated using gene set variation analysis (GSVA) and its efficacy in predicting immunotherapy outcomes was validated in two independent cohorts. High-scoring patients exhibited a 'hot' immune phenotype, correlating with enhanced immunotherapy efficacy. Key genes in our model, including C5AR1, APOE, CYR1P1, and SPP1, were implicated in COADREAD cell proliferation, invasion, and PD-L1 expression. These insights offer a novel approach to colorectal carcinoma treatment, emphasizing TLS targeting as a potential anti-tumor strategy.
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HMGB2-RAD21 Axis Promotes Fibro/Adipogenic Progenitor Proliferation and Regulates Fat Infiltration.
Intermuscular fat (IMF) infiltration is not only associated with myopathies and insulin resistance, but also serves as a key determinant of meat quality in the livestock industry. However, the molecular and cellular mechanisms influencing the intermuscular adipocyte abundance remain poorly understood. Based on porcine samples, we confirmed that the differentiation of intermuscular preadipocytes begins after birth, which prompted us to focus on the changes in the number of fibro/adipogenic progenitors (FAPs) during the embryonic stage. Using single-cell sequencing (ScRNA-seq) analysis of pig embryonic muscle, we constructed the first developmental atlas of embryonic FAPs and identified a distinct HMGB2+ subpopulation (FAPsHMGB2+) as a key determinant of FAP pool size. When HMGB2 is knocked out, both heterozygous and homozygous mice exhibit a remarkable reduction in the number of FAPs and impaired adipogenic potential. Correspondingly, the FAPsHMGB2+ were also found during muscle regeneration in mice. Unlike targeting C/EBPβ in vitro, HMGB2 governs FAP proliferation in vivo through targeting RAD21, a gene involved in DNA replication. Collectively, these findings provide novel insights into analyzing differences in IMF content and highlight potential targets for enhancing pork quality and mitigating pathological fat infiltration in skeletal muscles.
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Identification of an 11-miRNA-regulated and surface-protein genes signature predicts the prognosis of lung adenocarcinoma based on multi-omics study.
Lung adenocarcinoma (LUAD) is one of the most prevalent and lethal cancers worldwide, signifying a critical need for improved prognostic tools. A growing number of studies have highlighted the role of microRNAs (miRNAs) and their regulatory functions in tumorigenesis and cancer progression. In this context, we performed an extensive analysis of bulk RNA- and miRNA-sequencing to identify LUAD-associated prognostic genes. A risk score system based on 11 miRNA-regulated and surface-protein genes was developed, which was later validated by internally and externally using the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), respectively. Further single-cell RNA sequencing analysis revealed significant interactions between various cellular subpopulations within the tumor microenvironment, with the most pronounced differences observed between endothelial and epithelial cells. The mutational analysis highlighted TP53 as a key signaling pathway associated with the risk score. The study underscores that immune suppression, indicated by a positive association with regulatory T cells (Tregs) and an inverse correlation with M1-type macrophages, is prevalent in high-risk LUAD patients. These findings provide a promising prognostic tool for clinical outcomes of LUAD patients, facilitating future development of therapeutic strategies and enhancing our understanding of the regulatory function of miRNAs in LUAD.
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A sub-cluster of cancer cells indicates poor prognosis in advanced hepatocellular carcinoma.
BACKGROUND: For patients with advanced hepatocellular carcinoma (HCC), it is emergent to focus on elucidating different classifications of intratumoral heterogeneity and understanding the mechanisms of treatment resistance to improve prognosis. This study aims to classify the sub-clusters of cancer cells in patients diagnosed with advanced HCC, and identify the genes, pathways and microenvironment associated with prognosis. METHODS: Single-cell transcriptomic profiling were conducted on advanced HCC samples. Bulk RNA-seq transcriptome data were obtained from The Cancer Genome Atlas (TCGA) database. Prognosis analysis was performed for survival stratification within the identified sub-clusters. Enriched genes and pathways were determined, and the association and underlying mechanism of the identified sub-cluster of cancer cells were elucidate with other cellular components within advanced HCC tumor tissue. RESULTS: A total of 26,800 cells were obtained from two patients with advanced HCC. Seven sub-clusters were identified, and only the CancerCell 6 cluster were exhibited significant disparities in both overall survival (OS) and progression-free survival (PFS) rates according to the 370 HCC patients from the TCGA database. The CancerCell 6 cluster was associated with adenosine triphosphate (ATP)-related pathways and the high expression of pyruvate kinase M (PKM). It also demonstrated a strong interaction ability with mononuclear phagocytes (MPs). The MPs_MMP9 cluster showed strong interactions between the CancerCell 6 cluster and related signaling pathways of EDN and NOTCH, indicating a tendency toward M2 polarization. CONCLUSIONS: This study identified the CancerCell 6 cluster associated with a poor prognosis and characterized by ATP-related metabolism. This cluster demonstrated interactions with MPs inclined to M2 polarization.
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Single-cell RNA sequencing unveils CCDC86-driven immune modulation and antigen-presenting cell dynamics in head and neck squamous cell carcinoma.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with poor prognosis, partly due to an immunosuppressive tumor microenvironment. The immune-related gene CCDC86, selectively expressed in hematopoietic and antigen-presenting cells, has not been previously characterized in HNSCC. We aimed to delineate its expression pattern and immunological functions using integrated single-cell transcriptomic analysis. METHODS: Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and single-cell RNA-sequencing data (GEO: GSE139324) were integrated to assess CCDC86 expression, immune-cell specificity, and associated transcriptional programs in HNSCC. Differential expression, pathway enrichment, transcription factor regulon, and cell-cell communication analyses were conducted between CCDC86-high and CCDC86-low populations. The immune contexture and ligand-receptor interactions of CCDC86-expressing cells were evaluated to infer their roles in tumor-immune modulation. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis. RESULTS: CCDC86 was predominantly expressed in tumor-infiltrating antigen-presenting cells (APCs), including macrophages and dendritic cells. CCDC86-high APCs exhibited enhanced SPI1- and CEBPA-regulated transcriptional activity, metabolic reprogramming, and altered antigen-presentation signatures.Ligand-receptor network analysis revealed intensified interactions with T cells via both co-stimulatory (CD86-CD28) and checkpoint (PDCD1, CTLA4) pathways, suggesting dual immunomodulatory potential. Functionally, CCDC86-high APCs were associated with increased cytotoxic T-cell infiltration but concurrent T-cell dysfunction, implying that CCDC86 defines a specialized APC state that sustains chronic immune activation yet promotes tolerance within the tumor microenvironment. Additionally, qPCR validation following CCDC86 knockdown in FaDu cells was performed to confirm the transcriptional alterations of immune-related genes identified by bioinformatic analysis. CONCLUSIONS: CCDC86 acts as a key regulator of immune communication in HNSCC, orchestrating APC-T cell interactions and shaping an immunoregulatory niche. By linking antigen presentation with checkpoint signaling, CCDC86 contributes to immune evasion while maintaining local immune activation. These findings highlight CCDC86 as a promising prognostic biomarker and potential immunotherapeutic target in HNSCC.
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Single-cell RNA sequencing reveals a unique pericyte type associated with capillary dysfunction.
Background: Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However, the molecular profiles that govern the heterogeneity of pericytes have not been fully elucidated. Methods: Single-cell RNA sequencing was conducted on oxygen-induced proliferative retinopathy (OIR) model. Bioinformatics analysis was conducted to identify specific pericytes involved in capillary dysfunction. qRT-PCRs and western blots were conducted to detect Col1a1 expression pattern during capillary dysfunction. Matrigel co-culture assays, PI staining, and JC-1 staining was conducted to determine the role of Col1a1 in pericyte biology. IB4 and NG2 staining was conducted to determine the role of Col1a1 in capillary dysfunction. Results: We constructed an atlas of > 76,000 single-cell transcriptomes from 4 mouse retinas, which could be annotated to 10 distinct retinal cell types. Using the sub-clustering analysis, we further characterized retinal pericytes into 3 different subpopulations. Notably, GO and KEGG pathway analysis demonstrated that pericyte sub-population 2 was identified to be vulnerable to retinal capillary dysfunction. Based on the single-cell sequencing results, Col1a1 was identified as a marker gene of pericyte sub-population 2 and a promising therapeutic target for capillary dysfunction. Col1a1 was abundantly expressed in pericytes and its expression was obviously upregulated in OIR retinas. Col1a1 silencing could retard the recruitment of pericytes toward endothelial cells and aggravated hypoxia-induced pericyte apoptosis in vitro. Col1a1 silencing could reduce the size of neovascular area and avascular area in OIR retinas and suppressed pericyte-myofibroblast transition and endothelial-mesenchymal transition. Moreover, Col1a1 expression was up-regulated in the aqueous humor of the patients with proliferative diabetic retinopathy (PDR) or retinopathy of prematurity (ROP) and up-regulated in the proliferative membranes of PDR patients. Conclusions: These findings enhance the understanding of the complexity and heterogeneity of retinal cells and have important implications for future treatment of capillary dysfunction.
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Analysis of Prognosis and Immune Microenvironment of Protein Kinase C Substrate 80K-H in Diabetic Lung Cancer Patients.
BACKGROUND: A substantial association has been established between diabetes and an elevated risk of lung cancer. This study aimed to elucidate the prognosis and characterize alterations in the immune microenvironment linked to the protein kinase C substrate 80K-H (PRKCSH) gene in the context of diabetic lung cancer. METHODS: The expression profile of receptor for advanced glycation end products (RAGE) genes in lung adenocarcinoma (LUAD) and diabetic cohorts was analyzed utilizing data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). The methodological framework included single-sample gene set enrichment analysis (ssGSEA), hallmark pathway enrichment analysis, Pearson's correlation, and Wilcoxon tests, employing data from the Cancer Single Cell State Atlas (CancerSEA), tracking tumor immunophenotype (TIP) meta-server, and the Genomics of Drug Sensitivity in Cancer (GDSC) platform. PRKCSH-targeting small interfering RNA (siRNA) was synthesized and transfected into A549 cells. Functional validation of PRKCSH was conducted using real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting, methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and flow cytometry. RESULTS: The analysis identified five RAGE genes with dysregulated expression in both diabetic and LUAD conditions, which were significantly associated with the activation of signaling pathways and patterns of immune cell enrichment in diabetes. PRKCSH has been identified as an independent prognostic marker in LUAD, with associations with key biological processes such as cell cycle regulation, genomic instability responses, inflammatory mediation, and stem cell characteristics. Comprehensive pathway analysis revealed inverse relationships between PRKCSH expression and immune-related molecular mechanisms. Detailed immune profiling indicated reduced infiltration levels of various immune cell populations in association with elevated PRKCSH expression. Notably, increased PRKCSH activity in LUAD was linked to enhanced enzymatic pathway responses and greater therapeutic sensitivity to specific enzyme inhibitors. Experimental validation via gene silencing demonstrated that suppression of PRKCSH effectively reduced malignant cell proliferation while promoting apoptotic mechanisms in lung cancer models. CONCLUSIONS: This extensive investigation positioned PRKCSH as a critical prognostic biomarker and a promising therapeutic target for personalized immunotherapeutic strategies in the management of LUAD.
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Deciphering the composition and key driver genes of breast invasive micropapillary carcinoma by multi-omics analysis.
In this study, we delved into the intrinsic cellular components and transcriptomic signatures characterizing breast-invasive micropapillary carcinoma (IMPC). Employing bulk RNA sequencing, we conducted differential gene expression and functional profiles across breast cancer tissues. Single-cell transcriptome sequencing was performed on mixed IMPC samples. Moreover, a multicenter retrospective cohort of IMPC patients validated the critical role of KRT80. Our findings illuminated heightened activity in redox reactions and metabolism-related functions within IMPC compared to other tissue types. The single-cell atlas of IMPC demonstrated substantial heterogeneity predominantly driven by two distinct cell subsets: epithelioid and interstitial cells. Pseudotime analysis unveiled unique cell trajectories, and we found positive correlation between KRT80 expression and clinicopathological characteristics in IMPC. High KRT80 expression was associated with shorter overall survival for IMPC patients. This investigation unmasked extensive heterogeneity within breast IMPC tumors, delineating lineage distinctions across diverse cell clusters. It unveils potential prospective therapeutic targets with clinical relevance.
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Hypothesis-generating network toxicology analysis of potential molecular convergence between a polystyrene oligomer proxy and papillary thyroid carcinoma.
BACKGROUND: Polystyrene microplastics (PS-MPs) are emerging environmental contaminants with endocrine-disrupting and pro-inflammatory effects, but whether PS-MPs-associated molecular targets converge with papillary thyroid carcinoma (PTC) alterations remains unclear. This hypothesis-generating study aimed to identify candidate molecular networks and cellular contexts shared between a simplified polystyrene computational proxy and PTC. METHODS: Putative targets from CTD and from TargetNet/SwissTargetPrediction using a five-styrene-unit oligomer proxy were intersected with thyroid cancer-related genes from OMIM and GeneCards. Protein functional-association and enrichment analyses were followed by differential expression analysis in GSE33630 (45 normal and 49 PTC samples). LASSO and SVM-RFE identified core genes; stability was examined by repeated nested resampling conditional on the seven-gene candidate panel. Individual-gene tumor-normal discrimination was assessed in GSE33630 and GSE60542. Protein patterns were evaluated qualitatively in the Human Protein Atlas and preliminarily in 15 matched PTC-adjacent tissue pairs. CIBERSORT-estimated immune fractions and two single-cell datasets were analyzed as exploratory context. RESULTS: Among 144 putative proxy-associated targets and 2,139 thyroid cancer-related genes, 75 were shared. Seven candidates overlapped with 1,306 PTC differentially expressed genes, and BCL2, BAX, and FN1 were selected by both feature-selection methods and remained stable across the tested GeneCards thresholds and CTD-only sensitivity analysis. BCL2 was downregulated, whereas BAX and FN1 were upregulated in PTC; individual-gene AUCs were 0.963, 0.941, and 0.965 in GSE33630 and 0.942, 0.907, and 0.955 in GSE60542. HPA images and clinical IHC supported the same protein-level directions. After multiple-testing correction, only the CIBERSORT-estimated neutrophil fraction differed between groups (higher in PTC; q=0.0021). Single-cell analysis localized the three genes across epithelial, stromal, and immune compartments. CONCLUSION: BCL2, BAX, and FN1 are candidate molecular nodes at the convergence of polystyrene-proxy annotations and PTC-associated alterations. The findings do not demonstrate patient PS-MPs exposure, intact-particle effects, or causality, and require validation in material-characterized exposure experiments and exposure-aware clinical studies.