Molecular and radiopathologic spectrum between HCC and intrahepatic cholangiocarcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179443 | GEO | 2022/07/12
REPOSITORIES: GEO
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Project description:Langerhans cells (LCs) populate the mucosal epithelium, a major entry portal for pathogens, yet their ontogeny remains unclear. In contrast to skin LCs originating from self-renewing radioresistant embryonic precursors, we found that oral mucosal LCs derive from circulating radiosensitive precursors. Mucosal LCs can be segregated into CD103+CD11blow (CD103+LCs) and CD11b+CD103- (CD11b+LCs) subsets. We further demonstrated that similar to non-lymphoid dendritic cells (DCs), CD103+LCs originate from pre-DCs, whereas CD11b+LCs differentiate from both pre-DCs and monocytic precursors. Despite this ontogenetic discrepancy between skin and mucosal LCs, transcriptomic signature and immunological function of oral LCs highly resemble those of skin LCs but not DCs. These findings, along with their epithelial position, morphology and expression of LC-associated phenotype strongly suggest that oral mucosal LCs are genuine LCs. Collectively, in a tissue-dependent manner, murine LCs differentiate from at least three distinct precursors (embryonic, pre-DCs and monocytic) in steady state The following cells were isolated from mice (2-4 replicates): Lung DCs, mucosal CD103+ LC, mucosal CD11b+ LC, Skin LC. Transcriptome analysis was performed.
2015-08-31 | E-GEOD-68789 | biostudies-arrayexpress
Project description:Background & Aims: Combined HCC-iCCA is a rare liver tumor type and is often not well separated from HCC and iCCA. In this study, we analyzed major differences between combined HCC-iCCA and iCCA. Methods: We first characterized major differences between combined HCC-iCCA and iCCA by GSEA analysis. Consequently, we used CCl4 to induce chronic liver disease and subsequent liver carcinoma formation in mice. We forced the formation of combined HCC-iCCA through liver specific deletion of Rbpj, a key component of the Notch signaling pathway, in a Trp53 deficient background. Notch and p53 signaling pathways are involved in cellular differentiation processes and belong to the most affected pathways in liver carcinogenesis. Results: We show that combined HCC-iCCA can be separated from iCCA through differences in development related pathways, metabolism, cell to cell interaction and immune related pathways in human patients and in mice. Dysregulation of Notch signaling through a hepatocyte-specific Rbpj knockout resulted in an increased tumor burden and a high frequency of combined HCC-iCCA formation. In addition, hepatocytic loss of Rbpj forced M2 macrophage polarization and a tumor promoting environment. Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Our study highlights the importance of dysfunctional Notch signalling through Rbpj deletion in hepatocytes. Rbpj loss affects tumor differentiation and the tumor microenvironment which can be linked to a combined HCC-iCCA phenotype seen in human patients.
2023-08-31 | GSE212095 | GEO
Project description:DNA CpG methylation profiling of LC patients samples were performed to understand genotype to phenotype corrlelations , novel molecular subtypes and cell of origins Lung carcinoids (LCs) are rare and slow growing primary lung neoplasms that are understudied. Here, we performed targeted exome sequencing using a 354-cancer gene panel (n=29), mRNA sequencing (n=30) and DNA methylation assay (n=18) on macro-dissected lung carcinoids. The mutations we identified were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%) (MEN1, ARID1A, KMT2C and KMT2A were recurrently mutated) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed 3 robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be enriched and exclusively in the LC2 subtype (p-value<0.001). The LC3 subtype is predominately found at endobronchial lung and earlier age of diagnosis. Immunohistochemical staining of two biomarkers, ASCL1 and S100, is sufficient to stratify the three subtypes. This molecular classification of lung carcinoids into three subtypes may help improve treatment decision and clinical management.
2019-07-01 | GSE118132 | GEO
Project description:Atopic dermatitis (AD) is characterized by dysregulated T cell immunity and skin microbiome dysbiosis with predominance of Staphylococcus aureus (S. aureus). Emerging evidence suggests a role for S. aureus in exacerbating AD skin inflammation. Interestingly, specific glycosylation of S. aureus cell wall structures amplifies skin inflammation through interaction with Langerhans cells (LCs). However, the role of LCs in AD remains poorly characterized. Here, we performed single cell RNA-sequencing of primary epidermal LCs and dermal T cells isolated from skin biopsies of AD patients and healthy controls, alongside specific glycoanalysis of S. aureus strains isolated from the AD lesions. Our findings reveal four LC subpopulations, including two steady-state clusters (LC1 and LC1H) and two pro-inflammatory/matured subsets (LC2 and migratory LCs). The latter two subsets were enriched in AD skin. AD LCs showed enhanced expression of C-type lectin receptors, the high-affinity IgE receptor (FcεR1), and activation of prostaglandin and leukotrienes biosynthesis pathways, as well as upregulated transcriptional signatures related to T cell activation pathways and increased expression of CCL17 (specifically LC2) compared to healthy LCs. Correspondingly, T helper 2 and regulatory T cell populations were increased in AD lesions. Our study provides proof-of-concept for an active role of LCs in connecting the S. aureus-T cell axis in the AD inflammatory cycle.
2024-05-03 | GSE266239 | GEO
Project description:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-β synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs.
2014-08-01 | GSE59237 | GEO
Project description:The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. The ontogeny of human Langerhans cells (LCs) remains poorly characterized, in particular the nature of LC precursors and the factors that may drive LC differentiation. Through a systematic transcriptomic analysis of TSLP-activated dendritic cells (DCs), we unexpectedly identified markers that have been associated with a skin-homing potential as well as with a LC phenotype. We performed transcriptomic analysis of TSLP-activated blood DCs, as compared to freshly purified, Medium-, and TNF-activated DCs. Among TSLP up-regulated genes, we identified molecules associated with skin homing, LC phenotype, and LC function, as determined by a literature-based survey. Conversely, genes not expressed in LCs were not found among TSLP-induced genes. Further experiments showed that TGF-? synergized with TSLP leading to the differentiation of blood BDCA-1+ DCs into bona fide Birbeck granule-positive LCs. Dendritic cells (DC) were purified from the blood of healthy human donors. Each replicate comes from a different donor. There are 6 freshly purified samples (Control_0h), 4 DC samples cultured during 6h with no additional stimulus than the medium (Control_6h), 5 samples cultured during 6h with recombinant TSLP (Thymic Stromal Lymphopoietin at 20 ng/uL) (TSLP_6h) and 3 samples cultured during 6h with recombinant TNF (Tumor necrosis factor at 20 ng/mL) (TNF_6h).
2014-08-01 | E-GEOD-59237 | biostudies-arrayexpress
Project description:Langerhans cells (LCs) are skin-resident professional antigen-presenting dendritic cells (DCs) to maintain skin homeostasis. The number and function of LCs are significantly reduced during the skin aging processes, which is closely related to the aging-associated skin disorders. However, the reasons underlying the changes of LC features with age are uncertain. Mitochondria are well known to be the main powerhouse to regulate cell fitness and function, and a decline in mitochondrial quality and activity was associated with normal aging and correlated with the development of a wide range of age-related diseases. So far, it is unknown if mitochondrial abnormality is involved in skin disorders by regulating LC homeostasis. The mitochondrial transcription factor A (Tfam) acts as a nuclear-encoded transcription factor and plays a critical role in mitochondrial stabilization. To explore the role of mitochondrial quality in LC homeostasis, we generated the mice with conditional deletion of Tfam in LC lineage. We found that Tfam-deficient LCs exhibits mitochondrial abnormality including morphology and membrane permeability of mitochondria, decreased cell number as well as maturation, whereas increased phagocytosis and inflammatory response of LCs. Interestingly, age-LCs from human skin have lower Tfam expression compared to young-LCs, and have the similar features with Tfam-deficient LCs analyzed by scRNA sequence (HRA000395). Thus, our data highlight that Tfam-mediated mitochondrial stability is essential for epidermal LC maintenance and function, which might be explain the states of increased susceptible to skin infections and rising incidence of cutaneous tumor in the elder. This is the first time to investigate the effect of mitochondria abnormality on LC homeostasis, which might be helpful for therapeutic interventions in aging-associated skin pathologies.
2022-08-13 | GSE202351 | GEO
Project description:Background & Aims: Combined HCC/iCCA is a rare liver tumor type. We generated a transgenic mouse model (AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mouse) which developed next to HCC combined HCC/iCCA (cHCC/iCCA). We compared bilineal differentiated liver carcinoma cell lines generated from primary liver tumors of AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and transplanted them into C57BL/6J mice to monitor there agressiveness. We compared the geneexpression profile from those primary liver carcinoma cell lines with IFNγ treatment (pCCL-IFNγ) and without treatment (pCCL) with explanted primary carcinoma cell line (pCCL-ex). Results: Here we describe that elimination of HBs+ in pCCL by HBs/(Kb/S190-197)-specific CD8 T cells describes a potential immune escape mechanism for highly aggressive cHCC/iCCA-type liver carcinomas.
2023-05-23 | GSE215059 | GEO
Project description:TGF-β family ligands are key regulators of dendritic cell (DC) differentiation and activation. Epidermal Langerhans cells (LCs) require TGF-β family signaling for their differentiation and canonical TGF-β1 signaling secures a non-activated LC state. LCs reportedly control skin inflammation and are replenished from peripheral blood monocytes, which also give rise to pro-inflammatory monocyte-derived DCs (moDCs). By studying mechanisms in inflammation, we previously screened LCs vs moDCs for differentially expressed miRNAs. miR-424/503 was the most strongly inversely regulated (moDCs > LCs). We found that miR-424/503 is induced during moDC differentiation and promotes moDC differentiation in human and mouse. Inversely, forced repression of miR-424 during moDC differentiation facilitated TGF-β1-dependent LC differentiation. Mechanistically, miR-424/503 deficiency in monocyte/DC precursors leads to the induction of TGF-β1-response genes critical for LC differentiation. Therefore, the miR-424/503 gene cluster plays a decisive role in anti-inflammatory LC vs pro-inflammatory moDC differentiation from monocytes.
2021-03-27 | GSE169717 | GEO
Project description:The primary Langerhans cells (LCs) network in the mouse skin epidermis is established within a week after birth by differentiation of skin-seeded embryonic LC precursors into mature LCs. Through binding to distinct receptors, two members of the TGFβ superfamily, BMP7 and TGFβ1, initiate cellular signaling essential for inducing LCs differentiation and for preserving LCs in a quiescent state, respectively. However, how these two processes are regulated remains elusive. Here we show that loss of Cbfβ2, one of two RNA splice variants of the Cbfb gene, results in long-term persistence of embryonic-derived immature LCs after their developmental arrest at the transition into the EpCAM+ stage. This phenotype is caused by selective loss of TGFβ receptor signaling, essential for LCs differentiation with intact signaling, which maintains the quiescent state. Interestingly, skin residential Cbfβ2-defcient LC precursors could differentiate further upon transgenic Cbfβ2 expression, but only around postnatal period and not when it was expressed in one month old mice. Loss of developmental potency in the precursor cells was accompanied by diminished BMP7-BMPR1A signaling. Collectively, our results reveal an essential and selective requirement for the Cbfβ2 variant in LC differentiation, and provide a novel insight into how establishment and homeostasis of the LCs network is regulated.
2017-08-14 | GSE95487 | GEO