scholarly journals Resolving the spatial and cellular architecture of lung adenocarcinoma by multi-region single-cell sequencing

2020 ◽  
Author(s):  
Ansam Sinjab ◽  
Guangchun Han ◽  
Kieko Hara ◽  
Warapen Treekitkarnmongkol ◽  
Patrick Brennan ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Single Cell ◽  
Early Stage ◽  
Normal Lung ◽  
Cell Populations ◽  
T Regulatory Cell ◽  
Single Cell Sequencing ◽  
Normal Tissues ◽  
Inflammatory Dendritic Cells ◽  
Antigen Presenting

ABSTRACTLittle is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and fourteen multi-region normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to the LUADs. LUADs exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs driven by KRAS mutations. T regulatory cell phenotypes are increased in normal tissues with closer proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages and inflammatory dendritic cells. Further, the LUAD ecosystem harbors gain of ligand-receptor based interactions involving increased expression of CD24 antigen on epithelial cells and SIGLEC10 on myeloid subsets. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for treatment.Statement of significanceThe geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multi-region single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecological evolution LUAD from the lung that comprise high-potential targets for early interception.

scholarly journals Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5658
Author(s):  
Donát Alpár ◽  
Bálint Egyed ◽  
Csaba Bödör ◽  
Gábor T. Kovács
Keyword(s):  
High Resolution ◽  
Single Cell ◽  
Childhood Leukemia ◽  
Clinical Decision Making ◽  
Cellular Heterogeneity ◽  
Therapeutic Interventions ◽  
Cell Populations ◽  
Pediatric Leukemia ◽  
Single Cell Sequencing ◽  
Wide Range

Single-cell sequencing (SCS) provides high-resolution insight into the genomic, epigenomic, and transcriptomic landscape of oncohematological malignancies including pediatric leukemia, the most common type of childhood cancer. Besides broadening our biological understanding of cellular heterogeneity, sub-clonal architecture, and regulatory network of tumor cell populations, SCS can offer clinically relevant, detailed characterization of distinct compartments affected by leukemia and identify therapeutically exploitable vulnerabilities. In this review, we provide an overview of SCS studies focused on the high-resolution genomic and transcriptomic scrutiny of pediatric leukemia. Our aim is to investigate and summarize how different layers of single-cell omics approaches can expectedly support clinical decision making in the future. Although the clinical management of pediatric leukemia underwent a spectacular improvement during the past decades, resistant disease is a major cause of therapy failure. Currently, only a small proportion of childhood leukemia patients benefit from genomics-driven therapy, as 15–20% of them meet the indication criteria of on-label targeted agents, and their overall response rate falls in a relatively wide range (40–85%). The in-depth scrutiny of various cell populations influencing the development, progression, and treatment resistance of different disease subtypes can potentially uncover a wider range of driver mechanisms for innovative therapeutic interventions.

scholarly journals Reverse Regulation Between sFRP 5 and Dkk 1 Gene in Early Stage Lung Adenocancer

2021 ◽  
Author(s):  
Arife Zeybek ◽  
Necdet Oz ◽  
Serdar Kalemci ◽  
Kursad Tosun ◽  
Tuba Gökdoğan Edgünlü ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Tumor Tissue ◽  
Early Stage ◽  
Wnt Signaling Pathway ◽  
Normal Lung ◽  
Pcr Analysis ◽  
Related Protein ◽  
Expression Levels

Abstract Purpose: We aimed to examine the expression levels of the genes of APC (Adenomatous Polyposis Coli) 1, APC 2, Dkk (Dickkopf related protein) 1, Dkk -3, sFRP (Secreted frizzled-related protein) -2, sFRP-4, and sFRP-5 genes which play a role in the Wnt signaling pathway in lung adenocarcinoma and adjacent normal lung tissues, and to evaluate their relationship with clinical-pathological factors.Materials and methods: Between 2011 and 2018, the expression levels of the relevant genes in formalin-fixed paraffin-embedded tumor and adjacent intact lung tissue samples of 57 patients who were operated for lung adenocarcinoma were determined by Real-time PCR analysis. Results: The expression levels of the Dkk-1 gene in the tumor tissue, especially in stage I-II, were statistically significantly suppressed compared to normal tissue (p <0.025 ). Although Dkk-1 gene expression was suppressed in the tumor tissue of patients with early-stage lung adenocarcinoma, the level of expression of the sFRP-5 gene was found to be statistically significantly higher (p<0.039). Conclusion: In our study, between the sFRP-5 and Dkk-1 genes, known as the extracellular antagonist of the Wnt signaling pathway was found the reverse regulation. sFRP-5 gene was found as having an oncogenic role in adenocarcinoma development. Reverse regulation between these genes in early-stage lung adenocarcinoma may shed light on the mechanisms associated with the development of carcinogenesis. For that reason, clinically, this relationship needs to research in a larger series of pure adenocarcinoma and normal human lung tissues, separated by its stage, for potential therapeutic target or prognostic its significance.

scholarly journals Decreased IL-6 and NK Cells in Early-Stage Lung Adenocarcinoma Presenting as Ground-Glass Opacity

2021 ◽  
Vol 11 ◽  
Author(s):  
Pengfei Zhang ◽  
Boxue He ◽  
Qidong Cai ◽  
Guangxu Tu ◽  
Xiong Peng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Nk Cells ◽  
Nk Cell ◽  
Early Stage ◽  
Ground Glass Opacity ◽  
Tumor Infiltrating Lymphocytes ◽  
Ground Glass ◽  
Normal Lung ◽  
Sequencing Data ◽  
Primary Lung Adenocarcinoma

BackgroundLung ground-glass opacities (GGOs) are an early manifestation of lung adenocarcinoma. It is of great value to study the changes in the immune microenvironment of GGO to elucidate the occurrence and evolution of early lung adenocarcinoma. Although the changes of IL-6 and NK cells in lung adenocarcinoma have caught global attention, we have little appreciation for how IL-6 and NK cells in the lung GGO affect the progression of early lung adenocarcinoma.MethodsWe analyzed the RNA sequencing data of surgical specimens from 21 patients with GGO-featured primary lung adenocarcinoma and verified the changes in the expression of IL-6 and other important immune molecules in the TCGA and GEO databases. Next, we used flow cytometry to detect the protein expression levels of important Th1/Th2 cytokines in GGO and normal lung tissues and the changes in the composition ratio of tumor infiltrating lymphocytes (TILs). Then, we analyzed the effect of IL-6 on NK cells through organoid culture and immunofluorescence. Finally, we explored the changes of related molecules and pathway might be involved.ResultsIL-6 may play an important role in the tumor microenvironment of early lung adenocarcinoma. Further research confirmed that the decrease of IL-6 in GGO tissue is consistent with the changes in NK cells, and there seems to be a correlation between these two phenomena.ConclusionThe IL-6 expression status and NK cell levels of early lung adenocarcinoma as GGO are significantly reduced, and the stimulation of IL-6 can up-regulate or activate NK cells in GGO, providing new insights into the diagnosis and pathogenesis of early lung cancer.

scholarly journals Identification of Hub Genes, Modules and Metabolic Pathways Associated With Lung Adenocarcinoma: A System Biology Approach

2020 ◽  
Author(s):  
Raheleh Roudi ◽  
Behnaz Beikzadeh ◽  
Giandomenico Roviello ◽  
Alberto D'angelo ◽  
Morteza Hadizadeh
Keyword(s):  
Lung Adenocarcinoma ◽  
Metabolic Pathways ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Meta Analysis ◽  
Malignant Tumour ◽  
Gene Expression Omnibus ◽  
Normal Lung ◽  
Hub Genes ◽  
Unique Genes

Abstract Lung cancer is the most common and fatal malignant tumour worldwide with a five‐year overall survival rate of only 15%. Lung adenocarcinoma (LUAD) is a heterogeneous disease. The use of microarray datasets along with bioinformatics knowledge might help to clarify the expression profile of cancer, molecular markers for the initial screening of tumour and the underlying biological mechanisms. The present study is designed to identify differential expression genes and molecular mechanisms of LUAD compared to normal lung tissues using systems biology approaches.Methods Four GSE datasets (GSE75037, GSE63459, GSE32863 and GSE10072) were selected from the Gene Expression Omnibus (GEO) database. Data processing and meta-analysis were performed using the R statistical programming language, The differentially expressed genes (DEGs) associated with each stage were obtained. The common and unique DEGs between stages of LUAD and adjacent normal lung tissues were initiated by Venny tool. Common genes, including upregulated and downregulated genes, were then analyzed to a STRING database to obtain protein-protein interaction (PPI). STRING output was analyzed by MCODE and CytoHubba applications of Cytoscape to identify modules of co-expression and hub genes, respectively.Results The shared upregulated and downregulated DEGs among LUAD stages were 22 and 140 genes, respectively, when compared to normal lung tissues. Unique genes for each stage were also identified. The hub genes were PECAM1, TEK, CDH5, VWF and ANGPT1. Most of the top cluster genes were enriched for Gα(s) signalling events, GPCR ligand binding, class B/2 (Secretin family receptors), platelet activation, signalling and aggregation in the main three co-expression clusters. Most of the shared genes (16 genes) were enriched in the metabolic pathway of hemostasis. Meaningful signaling pathways for unique genes were found at each stage.Conclusions In the present study main three co-expression clusters, metabolic pathways and biological processes were identified to understand mechanisms underlying LUAD pathogenesis, development and progression at different stages. Unique upregulated and downregulated DEGs at each stage were identified with FERMT1 and SIX1 as specific early-stage diagnostic biomarkers for stage IB and IIB. 5 hub genes were observed, including PECAM1, TEK, CDH5, vWF and ANGPT1 which might be crucial for the onset and progression of LUAD.

scholarly journals Intratumoral molecular genetic heterogeneity of glioblastomas

2020 ◽  
Vol 9 (4) ◽  
pp. 5-11
Author(s):  
P.V. Nikitin ◽  
◽  
M.V. Ryzhova ◽  
A.A. Potapov ◽  
S.A. Galstyan ◽  
...  
Keyword(s):  
Single Cell ◽  
Genetic Heterogeneity ◽  
Tumor Therapy ◽  
Molecular Genetic ◽  
Experimental Treatment ◽  
Intratumoral Heterogeneity ◽  
Cell Populations ◽  
Malignant Neoplasms ◽  
Single Cell Sequencing

Intratumoral molecular genetic heterogeneity is not a less significant challenge in modern oncology than the intertumoral. The presence of cell populations within the same tumor, differing in their molecular properties, translated into phenotypic features of the cells, is one of the reasons for the inefficiency of many developments in the field of tumor therapy and the basis for the progression of malignant neoplasms. The issue under consideration is very relevant for glioblastoma (GBM) – being one of the deadliest human tumors; it practically does not lend itself to even promising experimental treatment methods. Therefore, this paper reviews intratumoral heterogeneity. The review in this aspect examines new experimental data, including those obtained using single-cell technologies, in particular, the key cell populations that make up the pool of tumor cells in glioblastoma, and their molecular metamodules, the presumptive role of some cell populations and their subpopulations in providing tumor malignancy properties. A promising groundwork for fundamentally new approaches to creating personalized diagnostic and therapeutic methods is indicated. Keywords: glioblastoma, intratumoral heterogeneity, glioblastoma genetics, single-cell sequencing

scholarly journals Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Oncogene ◽  
2021 ◽  
Author(s):  
Philip Bischoff ◽  
Alexandra Trinks ◽  
Benedikt Obermayer ◽  
Jan Patrick Pett ◽  
Jennifer Wiederspahn ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Single Cell ◽  
Rna Sequencing ◽  
Histological Grade ◽  
Cell Populations ◽  
Marker Genes ◽  
Single Cell Rna Sequencing

AbstractRecent developments in immuno-oncology demonstrate that not only cancer cells, but also the tumor microenvironment can guide precision medicine. A comprehensive and in-depth characterization of the tumor microenvironment is challenging since its cell populations are diverse and can be important even if scarce. To identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to ten human lung adenocarcinomas and ten normal control tissues. Our analyses revealed heterogeneous carcinoma cell transcriptomes reflecting histological grade and oncogenic pathway activities, and two distinct microenvironmental patterns. The immune-activated CP²E microenvironment was composed of cancer-associated myofibroblasts, proinflammatory monocyte-derived macrophages, plasmacytoid dendritic cells and exhausted CD8+ T cells, and was prognostically unfavorable. In contrast, the inert N³MC microenvironment was characterized by normal-like myofibroblasts, non-inflammatory monocyte-derived macrophages, NK cells, myeloid dendritic cells and conventional T cells, and was associated with a favorable prognosis. Microenvironmental marker genes and signatures identified in single-cell profiles had progonostic value in bulk tumor profiles. In summary, single-cell RNA profiling of lung adenocarcinoma provides additional prognostic information based on the microenvironment, and may help to predict therapy response and to reveal possible target cell populations for future therapeutic approaches.

scholarly journals Single-cell transcriptome reveals the redifferentiation trajectories of the early stage of de novo shoot regeneration in Arabidopsis thaliana

2022 ◽  
Author(s):  
Guangyu Liu ◽  
Jie Li ◽  
Jiming Li ◽  
Zhiyong Chen ◽  
Peisi Yuan ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Fate ◽  
Shoot Regeneration ◽  
De Novo ◽  
Developmental Process ◽  
Early Stage ◽  
Cell Populations ◽  
Cell Heterogeneity ◽  
Cell Transcriptome ◽  
Single Cell Transcriptome

De novo shoot regeneration from a callus plays a crucial role in both plant biotechnology and the fundamental research of plant cell totipotency. Recent studies have revealed many regulatory factors involved in this developmental process. However. our knowledge of the cell heterogeneity and cell fate transition during de novo shoot regeneration is still limited. Here, we performed time-series single-cell transcriptome experiments to reveal the cell heterogeneity and redifferentiation trajectories during the early stage of de novo shoot regeneration. Based on the single-cell transcriptome data of 35,669 cells at five-time points, we successfully determined seven major cell populations in this developmental process and reconstructed the redifferentiation trajectories. We found that all cell populations resembled root identities and undergone gradual cell-fate transitions. In detail, the totipotent callus cells differentiated into pluripotent QC-like cells and then gradually developed into less differentiated cells that have multiple root-like cell identities, such as pericycle-like cells. According to the reconstructed redifferentiation trajectories, we discovered that the canonical regeneration-related genes were dynamically expressed at certain stages of the redifferentiation process. Moreover, we also explored potential transcription factors and regulatory networks that might be involved in this process. The transcription factors detected at the initial stage, QC-like cells, and the end stage provided a valuable resource for future functional verifications. Overall, this dataset offers a unique glimpse into the early stages of de novo shoot regeneration, providing a foundation for a comprehensive analysis of the mechanism of de novo shoot regeneration.

scholarly journals PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment Combining Single-Cell and Bulk Sequencing Technology

2021 ◽  
Vol 12 ◽  
Author(s):  
Zheng Chen ◽  
Mincheng Yu ◽  
Jiuliang Yan ◽  
Lei Guo ◽  
Bo Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Malignant Cell ◽  
Cell Populations ◽  
Sequencing Data ◽  
Sequencing Technology ◽  
Immune Infiltration ◽  
Single Cell Sequencing

BackgroundCholangiocarcinoma was a highly malignant liver cancer with poor prognosis, and immune infiltration status was considered an important factor in response to immunotherapy. In this investigation, we tried to locate immune infiltration related genes of cholangiocarcinoma through combination of bulk-sequencing and single-cell sequencing technology.MethodsSingle sample gene set enrichment analysis was used to annotate immune infiltration status in datasets of TCGA CHOL, GSE32225, and GSE26566. Differentially expressed genes between high- and low-infiltrated groups in TCGA dataset were yielded and further compressed in other two datasets through backward stepwise regression in R environment. Single-cell sequencing data of GSE138709 was loaded by Seurat software and was used to examined the expression of infiltration-related gene set. Pathway changes in malignant cell populations were analyzed through scTPA web tool.ResultsThere were 43 genes differentially expressed between high- and low-immune infiltrated patients, and after further compression, PNOC and LAIR2 were significantly correlated with high immune infiltration status in cholangiocarcinoma. Through analysis of single-cell sequencing data, PNOC was mainly expressed by infiltrated B cells in tumor microenvironment, while LAIR2 was expressed by Treg cells and partial GZMB+ CD8 T cells, which were survival related and increased in tumor tissues. High B cell infiltration levels were related to better overall survival. Also, malignant cell populations demonstrated functionally different roles in tumor progression.ConclusionPNOC and LAIR2 were biomarkers for immune infiltration evaluation in cholangiocarcinoma. PNOC, expressed by B cells, could predict better survival of patients, while LAIR2 was a potential marker for exhaustive T cell populations, correlating with worse survival of patients.

scholarly journals Single cell sequencing analysis of lizard phagocytic cell populations and their role in tail regeneration

2020 ◽  
Vol 8 ◽  
pp. 100029
Author(s):  
Ricardo Londono ◽  
Sean Tighe ◽  
Beatrice Milnes ◽  
Christian DeMoya ◽  
Lina Maria Quijano ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Populations ◽  
Sequencing Analysis ◽  
Phagocytic Cell ◽  
Tail Regeneration ◽  
Single Cell Sequencing
Sign in / Sign up

Export Citation Format

Share Document