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Global characterization of megakaryocytes in bone marrow, peripheral blood, and cord blood by single-cell RNA sequencing.
Megakaryocytes (MK) are mainly derived from bone marrow and are mainly involved in platelet production. Studies have shown that MK derived from bone marrow may have immune function, and that MK from peripheral blood are associated with prostate cancer. Single-cell transcriptome sequencing can help us better understand the heterogeneity and potential function of MK cell populations in bone marrow (BM), peripheral Blood (PB), and cord blood (CB) of healthy and diseased people.We integrated more than 1.2 million single-cell transcriptome data from 132 samples of PB, BM, and CB from healthy individuals and patients from different dataset. We examined the MK (including MK and product of MK) by single-cell RNA sequencing data analysis methods and identification of MK-related protein expression by the Human Protein atlas. We investigate the relationship between the MK subtype and Non-Small Cell Lung Cancer (NSCLC) in 77 non-cancer and 402 NSCLC. We found that MK were widely distributed and the amount of MK in peripheral blood was more than that in bone marrow and there were specificity MK subtypes in peripheral blood. We found classical MK1 with typical MK characteristics and non-classical MK2 closely related to immunity which was the most common subtype in bone marrow and cord blood. Classical MK1 was closely related to Non-Small Cell Lung Cancer (NSCLC) and can be used as a diagnostic marker. MK2 may have potential adaptive immune function and play a role in tumor NSCLC and autoimmune diseases Systemic Lupus Erythematosus. MK have 14 subtypes and are widely distributed in PB, CB, and BM. MK subtypes are closely related to immunity and have potential to be a diagnostic indicator of NSCLC.
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Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma.
Alternative polyadenylation (APA) is a gene regulatory process that dictates mRNA 3'-UTR length, resulting in changes in mRNA stability and localization. APA is frequently disrupted in cancer and promotes tumorigenesis through altered expression of oncogenes and tumor suppressors. Pan-cancer analyses have revealed common APA events across the tumor landscape; however, little is known about tumor type-specific alterations that may uncover novel events and vulnerabilities. Here, we integrate RNA-sequencing data from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA events in 148 pancreatic ductal adenocarcinomas (PDACs). We report widespread, recurrent, and functionally relevant 3'-UTR alterations associated with gene expression changes of known and newly identified PDAC growth-promoting genes and experimentally validate the effects of these APA events on protein expression. We find enrichment for APA events in genes associated with known PDAC pathways, loss of tumor-suppressive miRNA binding sites, and increased heterogeneity in 3'-UTR forms of metabolic genes. Survival analyses reveal a subset of 3'-UTR alterations that independently characterize a poor prognostic cohort among PDAC patients. Finally, we identify and validate the casein kinase CSNK1A1 (also known as CK1alpha or CK1a) as an APA-regulated therapeutic target in PDAC. Knockdown or pharmacological inhibition of CSNK1A1 attenuates PDAC cell proliferation and clonogenic growth. Our single-cancer analysis reveals APA as an underappreciated driver of protumorigenic gene expression in PDAC via the loss of miRNA regulation.
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First-in-human single-cell and TCR atlas reveals peripheral immune remodeling before and after irreversible electroporation in prostate cancer.
BACKGROUND: Prostate cancer (PCa) is the second most common malignancy in men worldwide. Although radical prostatectomy effectively controls tumor progression, it often causes complications such as urinary incontinence and sexual dysfunction. Irreversible electroporation (IRE), a non-thermal ablation technique that preserves neurovascular structures, has emerged as a promising focal therapy and may induce systemic antitumor immunity through immunogenic cell death. However, the mechanisms and temporal dynamics of systemic immune responses to IRE in humans remain unclear. METHODS: This prospective study enrolled five patients with localized PCa (T2a-T2c). Peripheral blood samples were collected before and 7 days after IRE treatment. Single-cell RNA sequencing and T-cell receptor (TCR) repertoire profiling (10x Genomics) were performed to construct a high-resolution immune landscape. Integrated bioinformatic analyses-including Seurat/Harmony clustering, differential expression, functional enrichment, Gene Set Variation Analysis, transcription factor analysis, cell-cell communication (CellChat), and clonal tracking (Immunarch/scRepertoire)-were used to characterize systemic immune modulation following IRE. RESULTS: IRE induced bidirectional remodeling of the peripheral immune landscape. Myeloid cells, especially non-classical monocytes, increased in proportion and exhibited activation of inflammatory (interleukin-27), antiviral, complement, and antigen presentation pathways. T cells declined and exhibited reduced activation-associated and proliferation-associated transcriptional programs alongside enhanced survival-related signaling, consistent with a relative quiescent state of peripheral adaptive immunity at day 7. Natural killer cells showed elevated cytotoxic activity. TCR profiling revealed increased diversity and antigen-driven clonal expansion, while cell-cell communication shifted toward proinflammatory (TNF/SELPLG) and away from antigen-presenting (major histocompatibility complex (MHC)-I/CD40) interactions, indicating coordinated innate-adaptive rebalancing. CONCLUSION: This study is the first to map systemic immune dynamics after IRE in prostate cancer using single-cell analysis. 1 week after IRE, peripheral blood mononuclear cells show robust innate activation with concomitant attenuation of circulating T-cell activation/proliferation and reduced MHC-I/CD40-related communication, consistent with a time-dependent systemic immune rebalancing phase rather than sustained peak adaptive activation in blood. These findings support time-resolved immune monitoring and may help optimize the timing of IRE-based combination immunotherapy.
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Characterization of a G2M checkpoint-related gene model and subtypes associated with immunotherapy response for clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) presents challenges in early diagnosis and effective treatment. In this study, we aimed to establish a prognostic model based on G2M checkpoint-related genes and identify associated clusters in ccRCC through clinical bioinformatic analysis and experimental validation. Utilizing a single-cell RNA dataset (GSE159115) and bulk-sequencing data from The Cancer Genome Atlas (TCGA) database, we analyzed the G2M checkpoint pathway in ccRCC. Differential expression analysis identified 45 genes associated with the G2M checkpoint, leading to the construction of a predictive model with four key genes (E2F2, GTSE1, RAD54L, and UBE2C). The model demonstrated reliable predictive ability for 1-, 3-, and 5-year overall survival, with AUC values of 0.794, 0.790, and 0.794, respectively. Patients in the high-risk group exhibited a worse prognosis, accompanied by significant differences in immune cell infiltration, immune function, TIDE and IPS scores, and drug sensitivities. Two clusters of ccRCC were identified using the "ConsensusClusterPlus" package, cluster 1 exhibited a worse survival rate and was resistant to chemotherapeutic drugs of Axitinib, Erlotinib, Pazopanib, Sunitinib, and Temsirolimus, but not Sorafenib. Targeted experiments on RAD54L, a gene involved in DNA repair processes, revealed its crucial role in inhibiting proliferation, invasion, and migration in 786-O cells. In conclusion, our study offers valuable insights into the molecular mechanisms underlying ccRCC, identifying potential prognostic genes and molecular subtypes associated with the G2M checkpoint. These findings hold promise for guiding personalized treatment strategies in the management of ccRCC.
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Immune regulatory genes impact the hot/cold tumor microenvironment, affecting cancer treatment and patient outcomes.
BACKGROUND AND AIMS: Immunologically hot tumors, characterized by an inflamed tumor microenvironment (TME), contrast significantly with immunologically cold tumors. The identification of these tumor immune subtypes holds clinical significance, as hot tumors may exhibit improved prognoses and heightened responsiveness to checkpoint blockade therapy. Nevertheless, as yet there is no consensus regarding the clinically relevant definition of hot/cold tumors, and the influence of immune genes on the formation of hot/cold tumors remains poorly understood. METHODS: Data for 33 different types of cancer were obtained from The Cancer Genome Atlas database, and their immune composition was assessed using the CIBERSORT algorithm. Tumors were categorized as either hot or cold based on their distinct immune composition, ongoing immune response, and overall survival. A customized immunogram was created to identify important immunological characteristics. Kyoto Encyclopedia of Genes and Genomes and Hallmark pathway enrichment were evaluated through gene set variation analysis. Additionally, hub genes that regulate the tumor microenvironment were identified, and their expression patterns were analyzed using single-cell RNA sequencing. Furthermore, drug sensitivity and molecular docking analyses were performed to identify potential drug candidates capable of transforming cold tumors into hot tumors. For validation, a clinical cohort of patients diagnosed with pancreatic adenocarcinoma was examined using multiplex immunohistochemistry. RESULTS: We were able to differentiate between hot and cold tumors in various types of cancer (bladder urothelial carcinoma, pancreatic adenocarcinoma, and cervical squamous cell carcinoma) by analyzing the presence of CD8+ T cells, activated natural killer cells, and M2-type macrophages, as well as the cytolytic activity and T cell proliferation. Hub genes that regulate the TME, including PDCD1, CD276, and NT5E, were discovered. The increased expression of NT5E and its prognostic significance were confirmed through multiplex immunohistochemistry in pancreatic adenocarcinoma. Finally, dasatinib and tozasertib were identified as drug candidates capable of converting cold pancreatic adenocarcinoma tumors into hot tumors. CONCLUSION: In this study, we developed a framework for discerning clinically significant immune subtypes across various cancer types, further identifying several potential targets for converting cold tumors into hot tumors to enhance anticancer treatment efficacy.
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Proteome Landscape of Epithelial-to-Mesenchymal Transition (EMT) of Retinal Pigment Epithelium Shares Commonalities With Malignancy-Associated EMT.
Stress and injury to the retinal pigment epithelium (RPE) often lead to dedifferentiation and epithelial-to-mesenchymal transition (EMT). These processes have been implicated in several retinal diseases, including proliferative vitreoretinopathy, diabetic retinopathy, and age-related macular degeneration. Despite the importance of RPE-EMT and the large body of data characterizing malignancy-related EMT, comprehensive proteomic studies to define the protein changes and pathways underlying RPE-EMT have not been reported. This study sought to investigate the temporal protein expression changes that occur in a human-induced pluripotent stem cell-based RPE-EMT model. We utilized multiplexed isobaric tandem mass tag labeling followed by high-resolution tandem MS for precise and in-depth quantification of the RPE-EMT proteome. We have identified and quantified 7937 protein groups in our tandem mass tag-based MS analysis. We observed a total of 532 proteins that are differentially regulated during RPE-EMT. Furthermore, we integrated our proteomic data with prior transcriptomic (RNA-Seq) data to provide additional insights into RPE-EMT mechanisms. To validate these results, we have performed a label-free single-shot data-independent acquisition MS study. Our integrated analysis indicates both the commonality and uniqueness of RPE-EMT compared with malignancy-associated EMT. Our comparative analysis also revealed that multiple age-related macular degeneration-associated risk factors are differentially regulated during RPE-EMT. Together, our integrated dataset provides a comprehensive RPE-EMT atlas and resource for understanding the molecular signaling events and associated biological pathways that underlie RPE-EMT onset. This resource has already facilitated the identification of chemical modulators that could inhibit RPE-EMT, and it will hopefully aid in ongoing efforts to develop EMT inhibition as an approach for the treatment of retinal disease.
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Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition.
Cystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts more than 70,000 people. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most important determinant of morbidity and mortality. Here we report results from a multi-institute consortium in which single-cell transcriptomics were applied to define disease-related changes by comparing the proximal airway of CF donors (n = 19) undergoing transplantation for end-stage lung disease with that of previously healthy lung donors (n = 19). Disease-dependent differences observed include an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subsets coupled with an unexpected decrease in cycling basal cells. Our study yields a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.
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Integrated hypoxia and metabolic gene signature to predict clinical outcomes and therapeutic vulnerabilities in lung adenocarcinoma.
BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced non-small cell lung cancer (NSCLC), yet ~50% of lung adenocarcinoma (LUAD) patients exhibit primary or acquired resistance, underscoring the urgent need for predictive biomarkers. Hypoxia and metabolic reprogramming (HMR) are intertwined oncogenic hallmarks that reshape the tumor microenvironment (TME) and drive immune evasion, representing promising targets for signature development. Herein, we constructed an integrated HMR gene signature to predict clinical outcomes and therapeutic vulnerabilities in LUAD. METHODS: Transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were analyzed. Hypoxia and energy metabolism pathways were scored via single-sample gene set enrichment analysis (ssGSEA), and subtypes were stratified. A 9-gene prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression and validated across cohorts. Single-cell RNA (scRNA) data and in-house experimental validation explored associations between gene expression, immune microenvironment, and treatment outcomes. RESULTS: We developed a 9-gene HMR signature (RHOV, CYP4B1, KRT6A, TNS4, HMGA2, FIGF, SFTPB, TMPRSS11E, GRIA1) incorporating hypoxia and energy metabolism pathway activity. This signature robustly stratified patients into high- and low-risk groups with distinct overall survival [OS; hazard ratio (HR) =2.24, P<0.001]. High-risk patients exhibited enhanced immune evasion, characterized by elevated Tumor Immune Dysfunction and Exclusion (TIDE) scores (P<0.001) and a suppressed antitumor immune landscape, whereas distinct immune checkpoint expression patterns and subtype-specific drug sensitivities were observed between risk groups. scRNA sequencing revealed RHOV and TNS4 co-expressed with exhaustion markers (e.g., FOXP3, BTLA) and were enriched in non-major pathological response (non-MPR) patients. Validation in 39 ICI-treated NSCLC patients via quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunofluorescence (IF) confirmed that RHOV+ regulatory T cells and TNS4+ exhausted T cells were more abundant in poor responders. CONCLUSIONS: Overall, our integrated HMR signature exhibits robust prognostic and predictive value, unravels TME-driven ICI resistance mechanisms, and identifies subtype-specific therapeutic vulnerabilities. This tool has potential for clinical application, as it links HMR to clinical outcomes and provides novel insights to guide precision treatment strategies for LUAD patients.
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Tumor suppressive role of the epigenetic master regulator BRD3 in colorectal cancer.
Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.
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An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations.
Although well-differentiated thyroid carcinoma (WDTC) is characterized by a robust treatment response, aggressive subtypes, such as anaplastic thyroid carcinoma (ATC), remain highly lethal. To understand thyroid cancer evolution in both children and adults, we analyzed single-cell transcriptomes of 423,733 cells from 81 samples and spatially resolved key tumor and microenvironment populations across 28 tumors with spatial transcriptomics, including rare and unique composite WDTC/ATC tumors and pediatric diffuse sclerosing thyroid carcinomas. Additionally, we identified gene signatures of stromal cell populations in 5 large thyroid cancer bulk RNA-sequencing cohorts. Through this multi-institutional effort, we defined a population of POSTN+ myofibroblast cancer-associated fibroblasts (myCAFs) that are intimately associated with invasive tumor cells and correlate with poor prognosis, lymph node metastasis, and disease progression in thyroid carcinoma. We also revealed a population of inflammatory CAFs that are distant to tumor cells and are found in the inflammatory stromal microenvironment of autoimmune thyroiditis. Together, our study provides spatial profiling of thyroid cancer evolution in samples with mixed WDTC/ATC histopathology and identifies a prognostic myCAF subtype with potential clinical utility in predicting aggressive disease in both children and adults.