scholarly journals Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alma Andersson ◽  
Ludvig Larsson ◽  
Linnea Stenbeck ◽  
Fredrik Salmén ◽  
Anna Ehinger ◽  
...  
Keyword(s):  
Spatial Information ◽  
Cell Types ◽  
Interferon Response ◽  
Type I ◽  
Cellular Interactions ◽  
Her2 Positive ◽  
High Resolution Map ◽  
Functional Relevance ◽  
Macrophage Subset ◽  
Treatment And Diagnosis

AbstractIn the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases.

scholarly journals Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular Relationships

2020 ◽  
Author(s):  
Alma Andersson ◽  
Ludvig Larsson ◽  
Linnea Stenbeck ◽  
Fredrik Salmén ◽  
Anna Ehinger ◽  
...  
Keyword(s):  
Spatial Information ◽  
Breast Tumors ◽  
T Cell Subsets ◽  
Her2 Positive ◽  
Tertiary Lymphoid Structures ◽  
Novel Interactions ◽  
Lymphoid Structures ◽  
Functional Relevance ◽  
Treatment And Diagnosis ◽  
Cell Data

ABSTRACTIn the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra-and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. We integrate and spatially map tumor-associated types from single cell data to find: segregated epithelial cells, interactions between B and T-cells and myeloid cells, co-localization of macrophage and T-cell subsets. A model is constructed to infer presence of tertiary lymphoid structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define novel interactions between tumor-infiltrating cells in breast cancer and provide tools generalizing across tissues and diseases.

scholarly journals MicroRNA-deficient mouse embryonic stem cells acquire a functional interferon response

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jeroen Witteveldt ◽  
Lisanne I Knol ◽  
Sara Macias
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Embryonic Stem ◽  
Cell Types ◽  
Interferon Response ◽  
Central Component ◽  
Type I ◽  
Antiviral Mechanism

When mammalian cells detect a viral infection, they initiate a type I interferon (IFNs) response as part of their innate immune system. This antiviral mechanism is conserved in virtually all cell types, except for embryonic stem cells (ESCs) and oocytes which are intrinsically incapable of producing IFNs. Despite the importance of the IFN response to fight viral infections, the mechanisms regulating this pathway during pluripotency are still unknown. Here we show that, in the absence of miRNAs, ESCs acquire an active IFN response. Proteomic analysis identified MAVS, a central component of the IFN pathway, to be actively silenced by miRNAs and responsible for suppressing IFN expression in ESCs. Furthermore, we show that knocking out a single miRNA, miR-673, restores the antiviral response in ESCs through MAVS regulation. Our findings suggest that the interaction between miR-673 and MAVS acts as a switch to suppress the antiviral IFN during pluripotency and present genetic approaches to enhance their antiviral immunity.

scholarly journals Small Extracellular Vesicle Enrichment of a Retrotransposon-Derived Double-Stranded RNA: A Means to Avoid Autoinflammation?

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1136
Author(s):  
Marilou H. Barrios ◽  
Alexandra L. Garnham ◽  
Andrew D. Foers ◽  
Lesley Cheng-Sim ◽  
Seth L. Masters ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cell Types ◽  
Bioinformatic Analysis ◽  
Extracellular Vesicle ◽  
Interferon Response ◽  
Type I ◽  
Double Stranded Rna ◽  
Multiple Cell ◽  
Toxic Rna ◽  
Cellular Components

Small extracellular vesicles (SEVs) such as exosomes are released by multiple cell types. Originally believed to be a mechanism for selectively removing unwanted cellular components, SEVs have received increased attention in recent years for their ability to mediate intercellular communication. Apart from proteins and lipids, SEVs contain RNAs, but how RNAs are selectively loaded into SEVs remains poorly understood. To address this question, we profiled SEV RNAs from mouse dendritic cells using RNA-Seq and identified a long noncoding RNA of retroviral origin, VL30, which is highly enriched (>200-fold) in SEVs compared to parental cells. Bioinformatic analysis revealed that exosome-enriched isoforms of VL30 RNA contain a repetitive 26-nucleotide motif. This repeated motif is itself efficiently incorporated into SEVs, suggesting the likelihood that it directly promotes SEV loading. RNA folding analyses indicate that the motif is likely to form a long double-stranded RNA hairpin and, consistent with this, its overexpression was associated with induction of a potent type I interferon response. Taken together, we propose that preferential loading into SEVs of the VL30 RNA containing this immunostimulatory motif enables cells to remove a potentially toxic RNA and avoid autoinflammation. In this way, the original notion of SEVs as a cellular garbage bin should not be entirely discounted.

scholarly journals Nicastrin haploinsufficiency alters expression of type-I interferon-stimulated genes in two immortalized human cell lines

2018 ◽  
Author(s):  
Li Cao ◽  
David J. Morales-Heil ◽  
Elisha D. O. Roberson
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Rare Variants ◽  
Type I Interferon ◽  
Human Keratinocytes ◽  
Cell Types ◽  
Interferon Response ◽  
Luciferase Reporter ◽  
Type I ◽  
Loss Of Function

A.AbstractBackgroundHidradenitis suppurativa (HS) is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine-gland rich inverse skin, such as the buttocks, under the arms, and the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss-of-function rare variants in the γ-secretase complex component nicastrin (NCSTN).ObjectivesWe wanted to know what effect NCSTN haploinsufficiency has on human keratinocytes to assess potential mechanisms for lesion development.MethodsWe knocked down nicastrin using an shRNA construct in both a keratinocyte cell line (HEK001) and an embryonic kidney cell line (HEK293). We assessed differential gene expression using RNA microarray. We also generated a NCSTN heterozygous deletion in the HEK293 line using CRISPR/Cas9 genome-editing and assessed NFKB activity in this line using a luciferase reporter.ResultsThe keratinocyte NCSTN knockdown cell line demonstrated significantly increased expression of genes related to the type-I interferon response pathway when compared to controls. Both HEK001 and HEK293 knockdowns demonstrated evidence for altered growth. We observed a small, but significant increase in NFKB signaling in response to TNF treatment a HEK293 line genome-edited for reduced NCSTN.ConclusionsOur data suggest a role for increased keratinocyte inflammatory responsiveness in familial HS. Confirming this phenotype, and characterizing additional effects in different cell types, will require study beyond cell lines in primary cells and tissues.

scholarly journals GCNG: Graph convolutional networks for inferring cell-cell interactions

2019 ◽  
Author(s):  
Ye Yuan ◽  
Ziv Bar-Joseph
Keyword(s):  
Spatial Data ◽  
Spatial Information ◽  
Cell Types ◽  
Expression Vectors ◽  
Gene Interactions ◽  
Cellular Interactions ◽  
Expression Data ◽  
Neural Network Approach ◽  
Convolutional Networks ◽  
Transcriptomics Data

AbstractSeveral methods have been developed for inferring gene-gene interactions from expression data. To date, these methods mainly focused on intra-cellular interactions. The availability of high throughput spatial expression data opens the door to methods that can infer such interactions both within and between cells. However, the spatial data also raises several new challenges. These include issues related to the sparse, noisy expression vectors for each cell, the fact that several different cell types are often profiled, the definition of a neighborhood of cell and the relatively small number of extracellular interactions. To enable the identification of gene interactions between cells we extended a Graph Convolutional Neural network approach for Genes (GCNG). We encode the spatial information as a graph and use the network to combine it with the expression data using supervised training. Testing GCNG on spatial transcriptomics data we show that it improves upon prior methods suggested for this task and can propose novel pairs of extracellular interacting genes. Finally, we show that the output of GCNG can also be used for down-stream analysis including functional assignment.Supporting website with software and data: https://github.com/xiaoyeye/GCNG.

scholarly journals Nc886, a Novel Suppressor of the Type I Interferon Response Upon Pathogen Intrusion

2021 ◽  
Vol 22 (4) ◽  
pp. 2003
Author(s):  
Yeon-Su Lee ◽  
Xiaoyong Bao ◽  
Hwi-Ho Lee ◽  
Jiyoung Joan Jang ◽  
Enkhjin Saruuldalai ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cell Types ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Activator Protein 1 ◽  
Innate Immune Responses ◽  
Protein Kinase R ◽  
Crucial Component ◽  
Molecular Patterns

Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.

scholarly journals Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics

2020 ◽  
Author(s):  
Vitalii Kleshchevnikov ◽  
Artem Shmatko ◽  
Emma Dann ◽  
Alexander Aivazidis ◽  
Hamish W King ◽  
...  
Keyword(s):  
Single Cell ◽  
High Throughput ◽  
Spatial Organization ◽  
Immune Cell ◽  
Cell Types ◽  
Interferon Response ◽  
Tissue Cell ◽  
Analysis Tool ◽  
Cellular Interactions ◽  
And Function

AbstractThe spatial organization of cell types in tissues fundamentally shapes cellular interactions and function, but the high-throughput spatial mapping of complex tissues remains a challenge. We present сell2location, a principled and versatile Bayesian model that integrates single-cell and spatial transcriptomics to map cell types in situ in a comprehensive manner. We show that сell2location outperforms existing tools in accuracy and comprehensiveness and we demonstrate its utility by mapping two complex tissues. In the mouse brain, we use a new paired single nucleus and spatial RNA-sequencing dataset to map dozens of cell types and identify tissue regions in an automated manner. We discover novel regional astrocyte subtypes including fine subpopulations in the thalamus and hypothalamus. In the human lymph node, we resolve spatially interlaced immune cell states and identify co-located groups of cells underlying tissue organisation. We spatially map a rare pre-germinal centre B-cell population and predict putative cellular interactions relevant to the interferon response. Collectively our results demonstrate how сell2location can serve as a versatile first-line analysis tool to map tissue architectures in a high-throughput manner.

scholarly journals MicroRNA-deficient embryonic stem cells acquire a functional Interferon response

2018 ◽  
Author(s):  
Jeroen Witteveldt ◽  
Lisanne Knol ◽  
Sara Macias
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Embryonic Stem ◽  
Cell Types ◽  
Interferon Response ◽  
Central Component ◽  
Type I ◽  
Antiviral Mechanism

When mammalian cells detect a viral infection, they initiate a type-I Interferon (IFNs) response as part of their innate immune system. This antiviral mechanism is conserved in virtually all cell types, except for embryonic stem cells (ESCs) and oocytes which are intrinsically incapable of producing IFNs. Despite the importance of the IFN response to fight viral infections, the mechanisms regulating this pathway during pluripotency are still unknown. Here we show that, in the absence of miRNAs, ESCs acquire an active IFN response. Proteomic analysis identified MAVS, a central component of the IFN pathway, to be actively silenced by miRNAs and responsible for suppressing IFN expression in ESCs. Furthermore, we show that knocking out a single miRNA, miR-673, restores the antiviral response in ESCs through MAVS regulation. Our findings suggest that the interaction between miR-673 and MAVS acts as a switch to suppress the antiviral IFN during pluripotency and present genetic approaches to enhance their antiviral immunity.

scholarly journals Reconstruction of cell spatial organization based on ligand-receptor mediated self-assembly

2020 ◽  
Author(s):  
Xianwen Ren ◽  
Guojie Zhong ◽  
Qiming Zhang ◽  
Lei Zhang ◽  
Yujie Sun ◽  
...  
Keyword(s):  
Self Assembly ◽  
Spatial Organization ◽  
Spatial Information ◽  
Cell Types ◽  
Cellular Interaction ◽  
Great Promise ◽  
Cellular Interactions ◽  
Tumor Microenvironments ◽  
Tissue Dissociation

AbstractSingle-cell RNA sequencing (scRNA-seq) has revolutionized transcriptomic studies by providing unprecedented cellular and molecular throughputs, but spatial information of individual cells is lost during tissue dissociation. While imaging-based technologies such as in situ sequencing show great promise, technical difficulties currently limit their wide usage. Since cellular spatial organization is inherently encoded by cell identity and can be reconstructed, at least in part, by ligand-receptor interactions, here we present CSOmap, a computational strategy to infer cellular interaction from scRNA-seq. We show that CSOmap can successfully recapitulate the spatial organization of tumor microenvironments for multiple cancers and reveal molecular determinants of cellular interactions. Further, CSOmap readily simulates perturbation of genes or cell types to gain novel biological insights, especially into how immune cells interact in the tumor microenvironment. CSOmap can be widely applicable to interrogate cellular organizations based on scRNA-seq data for various tissues in diverse systems.

scholarly journals Activation of the Chicken Type I Interferon Response by Infectious Bronchitis Coronavirus

2014 ◽  
Vol 89 (2) ◽  
pp. 1156-1167 ◽  
Author(s):  
Joeri Kint ◽  
Marcela Fernandez-Gutierrez ◽  
Helena J. Maier ◽  
Paul Britton ◽  
Martijn A. Langereis ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Cell Types ◽  
Interferon Response ◽  
Type I ◽  
Content Type ◽  
Infectious Bronchitis ◽  
Tracheal Epithelial Cells ◽  
Chicken Cell ◽  
Host Virus Interactions ◽  
Virus Interactions

ABSTRACTCoronaviruses from both theAlphacoronavirusandBetacoronavirusgenera interfere with the type I interferon (IFN) response in various ways, ensuring the limited activation of the IFN response in most cell types. Of the gammacoronaviruses that mainly infect birds, little is known about the activation of the host immune response. We show that the prototypicalGammacoronavirus, infectious bronchitis virus (IBV), induces a delayed activation of the IFN response in primary renal cells, tracheal epithelial cells, and a chicken cell line. In fact,Ifnβexpression is delayed with respect to the peak of viral replication and the accompanying accumulation of double-stranded RNA (dsRNA). In addition, we demonstrate that MDA5 is the primary sensor forGammacoronavirusinfections in chicken cells. Furthermore, we provide evidence that accessory proteins 3a and 3b of IBV modulate the response at the transcriptional and translational levels. Finally, we show that, despite the lack of activation of the IFN response during the early phase of IBV infection, the signaling of nonself dsRNA through both MDA5 and TLR3 remains intact in IBV-infected cells. Taken together, this study provides the first comprehensive analysis of host-virus interactions of aGammacoronaviruswith avian innate immune responses.IMPORTANCEOur results demonstrate that IBV has evolved multiple strategies to avoid the activation of the type I interferon response. Taken together, the present study closes a gap in the understanding of host-IBV interaction and paves the way for further characterization of the mechanisms underlying immune evasion strategies as well as the pathogenesis of gammacoronaviruses.

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