Single-cell transcriptomics reveals long noncoding RNAs associated with tumor biology and the microenvironment in pancreatic cancer
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PROVIDER: S-EPMC10664695 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Recent developments of single cell transcriptome profiling methods have led to the realization that many seemingly homogeneous cells have surprising levels of expression variability. The biological implications of the high degree of variability is unclear but one possibility is that many genes are restricted in expression to small lineages of cells, suggesting the existence of many more cell types than previously estimated. Noncoding RNA (ncRNA) are thought to be key parts of gene regulatory processes and their single cell expression patterns may help to dissect the biological function of single cell variability. Technology for measuring ncRNA in single cell is still in development and most of the current single cell datasets have reliable measurements for only long noncoding RNA (lncRNA). Most works report that lncRNAs show lineage-specific restricted expression patterns, which suggest that they might determine, at least in part, lineage fates and cell subtypes. However, evidence is still inconclusive as to whether lncRNAs and other ncRNAs are more lineage-specific than protein-coding genes. Nevertheless, measurement of ncRNAs in single cells will be important for studies of cell types and single cell function. WIREs RNA 2017, 8:e1433. doi: 10.1002/wrna.1433 For further resources related to this article, please visit the WIREs website.
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Project description:IntroductionThe complexity of tumor cell subclonal structure has been extensively investigated in hepatocellular carcinoma. However, the role of subclonal complexity in reshaping the tumor microenvironment (TME) remains poorly understood.MethodsWe integrated single-cell transcriptome sequencing data from four independent HCC cohorts, involving 30 samples, to decode the associations between tumor subclonal complexity and the TME. We proposed a robust metric to accurately quantify the degree of subclonal complexity for each sample based on discrete copy number variations (CNVs) profiles.ResultsWe found that tumor cells in the high-complexity group originated from the cell lineage with FGB overexpression and exhibited high levels of transcription factors associated with poor survival. In contrast, tumor cells in low-complexity patients showed activation of more hallmark signaling pathways, more active cell-cell communications within the TME and a higher immune activation status. Additionally, cytokines signaling activity analysis suggested a link between HMGB1 expressed by a specific endothelial subtype and T cell proliferation.DiscussionOur study sheds light on the intricate relationship between the complexity of subclonal structure and the TME, offering novel insights into potential therapeutic targets for HCC.
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Project description:Noncoding RNAs are proclaimed to be expressed in various cancer types and one such type is found to be pancreatic ductal adenocarcinoma (PDAC). The long noncoding RNAs (LncRNAs) affect the migration, invasion, and growth of tumor cells by playing important roles in the process of epigenesis, post-transcription, and transcriptional regulation along with the maintenance of apoptosis and cell cycle. It is quite subtle whether the alterations in lncRNAs would impact PDAC progression and development. This review throws a spotlight on the lncRNAs associated with tumor functions: MALAT-1, HOTAIR, HOXA13, H19, LINC01559, LINC00460, SNHG14, SNHG16, DLX6-AS1, MSC-AS1, ABHD11-AS1, DUXAP8, DANCR, XIST, DLEU2, etc. are upregulated lncRNAs whereas GAS5, HMlincRNA717, MIAT, LINC01111, lncRNA KCNK15-AS1, etc. are downregulated lncRNAs inhibiting the invasion and progression of PDAC. These data provided helps in the assessment of lncRNAs in the development, metastasis, and occurrence of PDAC and also play a vital role in the evolution of biomarkers and therapeutic agents for the treatment of PDAC.
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Project description:A growing number of gene-centric studies have highlighted the emerging significance of lncRNAs in cancer. However, these studies primarily focus on a single cancer type. Therefore, we conducted a pan-cancer analysis of lncRNAs comparing tumor and matched normal expression levels using RNA-Seq data from ? 3,000 patients in 8 solid tumor types. While the majority of differentially expressed lncRNAs display tissue-specific expression we discovered 229 lncRNAs with outlier or differential expression across multiple cancers, which we refer to as 'onco-lncRNAs'. Due to their consistent altered expression, we hypothesize that these onco-lncRNAs may have conserved oncogenic and tumor suppressive functions across cancers. To address this, we associated the onco-lncRNAs in biological processes based on their co-expressed protein coding genes. To validate our predictions, we experimentally confirmed cell growth dependence of 2 novel oncogenic lncRNAs, onco-lncRNA-3 and onco-lncRNA-12, and a previously identified lncRNA CCAT1. Overall, we discovered lncRNAs that may have broad oncogenic and tumor suppressor roles that could significantly advance our understanding of cancer lncRNA biology.
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Project description:Normal skeletal development requires tight coordination of transcriptional networks, signaling pathways, and biomechanical cues, and many of these pathways are dysregulated in pathological conditions affecting cartilage and bone. Recently, a significant role has been identified for long noncoding RNAs (lncRNAs) in developing and maintaining cellular phenotypes, and improvements in sequencing technologies have led to the identification of thousands of lncRNAs across diverse cell types, including the cells within cartilage and bone. It is clear that lncRNAs play critical roles in regulating gene expression. For example, they can function as epigenetic regulators in the nucleus via chromatin modulation to control gene transcription, or in the cytoplasm, where they can function as scaffolds for protein-binding partners or modulate the activity of other coding and noncoding RNAs. In this review, we discuss the growing list of lncRNAs involved in normal development and/or homeostasis of the skeletal system, the potential mechanisms by which these lncRNAs might function, and recent improvements in the methodologies available to study lncRNA functions in vitro and in vivo. Finally, we address the likely utility of lncRNAs as biomarkers and therapeutic targets for diseases of the skeletal system, including osteoarthritis, osteoporosis, and in cancers of the skeletal system.
| S-EPMC5301950 | biostudies-literature
Project description:The nucleolus, the largest subcompartment of the nucleus, stands out from the nucleoplasm due to its exceptionally high local RNA and low DNA concentrations. Within this central hub of nuclear RNA metabolism, ribosome biogenesis is the most prominent ribonucleoprotein (RNP) biogenesis process, critically determining the structure and function of the nucleolus. However, recent studies have shed light on other roles of the nucleolus, exploring the interplay with various noncoding RNAs that are not directly involved in ribosome synthesis. This review focuses on this intriguing topic and summarizes the techniques to study and the latest findings on nucleolar long noncoding RNAs (lncRNAs) as well as microRNAs (miRNAs) in the context of nucleolus biology beyond ribosome biogenesis. We particularly focus on the multifaceted roles of the nucleolus and noncoding RNAs in physiology and tumor biology.
| S-EPMC10730139 | biostudies-literature
Project description:Osteosarcoma (OS), which occurs most commonly in adolescents, is associated with a high degree of malignancy and poor prognosis. In order to develop an accurate treatment for OS, a deeper understanding of its complex tumor microenvironment (TME) is required. In the present study, tissues were isolated from six patients with OS, and then subjected to single-cell RNA sequencing (scRNA-seq) using a 10× Genomics platform. Multiplex immunofluorescence staining was subsequently used to validate the subsets identified by scRNA-seq. ScRNA-seq of six patients with OS was performed prior to neoadjuvant chemotherapy, and data were obtained on 29,278 cells. A total of nine major cell types were identified, and the single-cell transcriptional map of OS was subsequently revealed. Identified osteoblastic OS cells were divided into five subsets, and the subsets of those osteoblastic OS cells with significant prognostic correlation were determined using a deconvolution algorithm. Thereby, different transcription patterns in the cellular subtypes of osteoblastic OS cells were reported, and key transcription factors associated with survival prognosis were identified. Furthermore, the regulation of osteolysis by osteoblastic OS cells via receptor activator of nuclear factor kappa-B ligand was revealed. Furthermore, the role of osteoblastic OS cells in regulating angiogenesis through vascular endothelial growth factor-A was revealed. C3_TXNIP+ macrophages and C5_IFIT1+ macrophages were found to regulate regulatory T cells and participate in CD8+ T cell exhaustion, illustrating the possibility of immunotherapy that could target CD8+ T cells and macrophages. Our findings here show that the role of C1_osteoblastic OS cells in OS is to promote osteolysis and angiogenesis, and this is associated with survival prognosis. In addition, T cell depletion is an important feature of OS. More importantly, the present study provided a valuable resource for the in-depth study of the heterogeneity of the OS TME.
| S-EPMC8335545 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignant tumor characterized by a complex tumor microenvironment (TME) with significant heterogeneity, posing immense challenges for devising effective therapeutic strategies. This study aims to elucidate the dynamic changes in the TME during PDAC progression and develop a prognostic model using single-cell RNA sequencing (scRNA-seq) data. We utilized a previously published comprehensive dataset comprising 31 samples (including 8 PDAC I, 9 PDAC II, 6 PDAC III, and 8 PDAC IV) to characterize the changes in TME composition with PDAC progression through advanced scRNA-seq analysis. We found that as cancer progresses, immune cells gradually become a predominant component in late-stage PDAC. We defined a novel Treg and exhausted T cell signature gene, TNFRSF4. Additionally, we identified a prognostic gene set (RPS10, MIF, MT-ATP6, CSTB, IFI30, NPC2, BTG1, CTSD, FCGR2A, SEC61G, IER3, HSPB1, HMOX1, and ZFP36L1) and differentiated high-risk from low-risk PDAC patients based on median risk score threshold. Based on these findings, we developed a novel prognostic model that identifies poorer prognosis in high-risk groups. Furthermore, our analysis revealed significant interactions between cells at different stages of PDAC and identified three promising therapeutic agents (XR-11576, Ixabepilone, and AMONAFIDE) based on correlated genes. Finally, molecular docking studies validated their potential by confirming stable binding with key protein targets. This study not only provides insights into the evolving TME of PDAC but also offers a new prognostic model and potential therapeutic strategies, contributing to improved management and treatment of this aggressive cancer.
| S-EPMC11788434 | biostudies-literature
Project description:BackgroundThe main immune cells in GBM are tumor-associated macrophages (TAMs). Thus far, the studies investigating the activation status of TAM in GBM are mainly limited to bulk RNA analyses of individual tumor biopsies. The activation states and transcriptional signatures of TAMs in GBM remain poorly characterized.MethodsWe comprehensively analyzed single-cell RNA-sequencing data, covering a total of 16,201 cells, to clarify the relative proportions of the immune cells infiltrating GBMs. The origin and TAM states in GBM were characterized using the expression profiles of differential marker genes. The vital transcription factors were examined by SCENIC analysis. By comparing the variable gene expression patterns in different clusters and cell types, we identified components and characteristics of TAMs unique to each GBM subtype. Meanwhile, we interrogated the correlation between SPI1 expression and macrophage infiltration in the TCGA-GBM dataset.ResultsThe expression patterns of TMEM119 and MHC-II can be utilized to distinguish the origin and activation states of TAMs. In TCGA-Mixed tumors, almost all TAMs were bone marrow-derived macrophages. The TAMs in TCGA-proneural tumors were characterized by primed microglia. A different composition was observed in TCGA-classical tumors, which were infiltrated by repressed microglia. Our results further identified SPI1 as a crucial regulon and potential immunotherapeutic target important for TAM maturation and polarization in GBM.ConclusionsWe describe the immune landscape of human GBM at a single-cell level and define a novel categorization scheme for TAMs in GBM. The immunotherapy against SPI1 would reprogram the immune environment of GBM and enhance the treatment effect of conventional chemotherapy drugs.
| S-EPMC8382282 | biostudies-literature
Project description:Ocular neovascularization is a pathological sequel of multiple eye diseases. Based on the anatomical site into which the abnormal neovessels grow, ocular neovascularization can be categorized into corneal neovascularization, choroidal neovascularization, and retinal neovascularization. Each category is intractable, and may lead to blindness if not appropriately treated. However, the current therapeutic modalities, including laser photocoagulation, vitrectomy surgery, and anti-VEGF drugs, raise concerns due to limited efficacy, damage on retinal parenchyma and vasculature, and the patients' unresponsiveness to the treatments. Therefore, the in-depth study on pathogenesis of and the search for novel therapeutic targets to the ocular neovascularization are needed. During the last 10 years or so, a large number of literatures have emerged indicating a critical role of noncoding RNAs, particularly microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), in the pathogenesis and regulation of the ocular neovascularization. This review summarizes the current understanding of the biosynthesis and functions of the miRNAs and lncRNAs, the regulation of the miRNAs and lncRNAs in neovascular eye diseases, as well as the roles of these noncoding RNAs in the disease models of ocular neovascularization, in the hope that it could provide clues for the pathogenesis of and molecular targets to the ocular neovascularization.
| S-EPMC5566112 | biostudies-other