Close proximity between cytotoxic T lymphocytes and tumour cells is required for effective immunotherapy. However, what controls the spatial distribution of T cells in the tumour microenvironment is ...not well understood. Here we couple digital pathology and transcriptome analysis on a large ovarian tumour cohort and develop a machine learning approach to molecularly classify and characterize tumour-immune phenotypes. Our study identifies two important hallmarks characterizing T cell excluded tumours: 1) loss of antigen presentation on tumour cells and 2) upregulation of TGFβ and activated stroma. Furthermore, we identify TGFβ as an important mediator of T cell exclusion. TGFβ reduces MHC-I expression in ovarian cancer cells in vitro. TGFβ also activates fibroblasts and induces extracellular matrix production as a potential physical barrier to hinder T cell infiltration. Our findings indicate that targeting TGFβ might be a promising strategy to overcome T cell exclusion and improve clinical benefits of cancer immunotherapy.
The aim of this study was to gain further investigation of non-small cell lung cancer (NSCLC) tumorigenesis and identify biomarkers for clinical management of patients through comprehensive ...bioinformatics analysis.
miRNA and mRNA microarray datasets were downloaded from GEO (Gene Expression Omnibus) database under the accession number GSE102286 and GSE101929, respectively. Genes and miRNAs with differential expression were identified in NSCLC samples compared with controls, respectively. The interaction between differentially expressed genes (DEGs) and differentially expressed miRNAs (DEmiRs) was predicted, followed by functional enrichment analysis, and construction of miRNA-gene regulatory network, protein-protein interaction (PPI) network, and competing endogenous RNA (ceRNA) network. Through comprehensive bioinformatics analysis, we anticipate to find novel therapeutic targets and biomarkers for NSCLC.
A total of 123 DEmiRs (5 up- and 118 down-regulated miRNAs) and 924 DEGs (309 up- and 615 down-regulated genes) were identified. These genes and miRNAs were significantly involved in different pathways including adherens junction, relaxin signaling pathway, and axon guidance. Furthermore, hsa-miR-9-5p, has-miR-196a-5p and hsa-miR-31-5p, as well as hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p were shown to have higher degree in the miRNA-gene regulatory network and ceRNA network, respectively. Furthermore, BIRC5 and FGF2, as well as RTKN2 and SLIT3 were hubs in the PPI network and ceRNA network, respectively.
Several pathways (adherens junction, relaxin signaling pathway, and axon guidance) miRNAs (hsa-miR-9-5p, has-miR-196a-5p, hsa-miR-31-5p, hsa-miR-1, hsa-miR-218-5p and hsa-miR-135a-5p) and genes (BIRC5, FGF2, RTKN2 and SLIT3) may play important roles in the pathogenesis of NSCLC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Spatiotemporal pattern of the simulated soil moisture in 0–289 cm soil layer for the control run (LC2000) and sensitivity simulation experiment (LC2015) on the Loess Plateau of China. Areas with a ...significant change (p < 0.05) based on t-test are stippled.
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•Soil moisture (SM) in different soil layers showed significant decreasing trends.•Sensitivity experiments were designed to quantify the SM status.•Vegetation restoration caused SM reduction in subsurface and deeper soil layers.•Significant decrease in SM occurred in eastern LP where forest cover increased.•SM reduction due to vegetation restoration did not exhibit seasonal differences.
Characterizing soil moisture (SM) dynamics is a prerequisite for implementing sustainable vegetation restoration on the Loess Plateau (LP) of China. However, quantifying SM variation both spatially and temporally remains a challenge due to various driving factors and the complexity of land surface processes. This study was designed to investigate the magnitude and trends of SM variation due to vegetation restoration in soil profiles at the regional scale using earth system reanalysis data and the Community Land Model (CLM). The results indicated that the surface layer SM had positive responses to vegetation restoration, while the SM in the subsurface and deeper soil layers had negative responses. The area-averaged annual mean SM under vegetated condition in 2015 (LC2015) was less than that in 2000 (LC2000), with a magnitude of 11.7 mm. Spatially, almost the whole LP region exhibited decreased SM in the 100–289 cm layer in the LC2015 simulation, and significant differences were detected on the southeastern LP, where the forest coverage clearly increased from 2000 to 2015, with the decreased annual mean SM ranging from 20 to 40 mm. These differences were also reflected in the seasonal SM, showing that SM in the 100–289 cm layer in the LC2015 simulation was less than that in the LC2000 simulation, with significant differences of 11.5 mm, 11.7 mm, 11.9 mm and 11.7 mm for spring, summer, autumn and winter, respectively (p < 0.05). Notably, the temporal variabilities in SM in both the LC2000 and LC2015 simulations showed a decreasing trend during the simulation period, and the decreasing magnitudes increased as the soil depth increased; the largest decreasing gradient was approximately 2.1 mm/year in the 100–289 cm layer. These findings implied that vegetation restoration on the LP led to a significant reduction in SM, that was difficult to replenish by local precipitation and in turn had negative effects on plant growth and water resources.
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning ...these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
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•OXPHOS and IFN gene sets are enriched in infiltrated and excluded tumor cells.•Pre-dysfunctional CD8+ GZMK T cells are enriched in excluded tumors.•FCN1 monocytes and immature MARCO macrophages are enriched in desert tumors.•CXCL16 is expressed primarily by infiltrated tumor cells and CXCR6 by T cells.
Hornburg et al. dissected the composition of the ovarian tumor microenvironment by scRNA-seq to define the underlying biology of the T cell infiltration pattern, namely the tumor immune phenotypes. The identified features, including the enrichment of immature myeloid cells in desert tumors, may help inform immunotherapeutic strategies in ovarian cancer.
There are remarkable disparities among patients of different races with prostate cancer; however, the mechanism underlying this difference remains unclear. Here, we present a comprehensive landscape ...of the transcriptome profiles of 14 primary prostate cancers and their paired normal counterparts from the Chinese population using RNA-seq, revealing tremendous diversity across prostate cancer transcriptomes with respect to gene fusions, long noncoding RNAs （long ncRNA）, alternative splicing and somatic mutations. Three of the 14 tumors （21.4%） harbored a TM- PRSS2-ERG fusion, and the low prevalence of this fusion in Chinese patients was further confirmed in an additional tumor set （10/54=18.5%）. Notably, two novel gene fusions, CTAGE5-KHDRBS3 （20/54=37%） and USP9Y-TTTY15 （19/54=35.2%）, occurred frequently in our patient cohort. Further systematic transcriptional profiling identified nu- merous long ncRNAs that were differentially expressed in the tumors. An analysis of the correlation between expres- sion of long ncRNA and genes suggested that long ncRNAs may have functions beyond transcriptional regulation. This study yielded new insights into the pathogenesis of prostate cancer in the Chinese population.
Long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) has been reported to play important roles in the development and progression of multiple human malignancies. However, the ...functional role and molecular mechanism of CCAT1 on gefitinib resistance in non-small cell lung cancer (NSCLC) are largely unclear. The aim of this study is to explore the roles of CCAT1 on gefitinib resistance in NSCLC and to explore the underlying mechanisms. The quantitative real-time PCR (qRT-PCR) analysis was to investigate the expression pattern of CCAT1 in gefitinib-resistant NSCLC patient tissues and cell lines, and then the effects of CCAT1 on gefitinib resistance of NSCLC in vitro and in vivo. Furthermore, bioinformatics online program predictions and luciferase reporter assay were used to validate the association of CCAT1 and miR-218 in NSCLC cells. In this study, CCAT1 was observed to be upregulated in gefitinib-resistant patient tissues and cell lines. In vitro and in vivo experiments demonstrated that CCAT1 knockdown impaired cell proliferation and promoted the gefitinib-induced cell apoptosis. Furthermore, we demonstrated that CCAT1 acts as a sponge for miR-218, and verified that HOXA1 is a novel target of miR-218. These results suggest that CCAT1 may serve as a promising therapeutic target for the treatment of epidermal growth factor receptor (EGFR) plus NSCLC patients.
Recurrent R-spondin fusions in colon cancer SESHAGIRI, Somasekar; STAWISKI, Eric W; GUILLORY, Joseph ...
Nature (London),
08/2012, Letnik:
488, Številka:
7413
Journal Article
Recenzirano
Odprti dostop
Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by ...applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples ...consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ∼27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Vascular smooth muscle cell (VSMC) proliferation and migration are vital to atherosclerosis (AS) development and plaque rupture. MicroRNA-377-3p (miR-377-3p) has been reported to inhibit AS in ...apolipoprotein E knockout (ApoE-/-) mice. Herein, the mechanism underlying the effect of miR-377-3p on alleviating AS is explored. In vivo experiments, ApoE-/- mice were fed with high-fat diet (HFD) to induce AS and treated with miR-377-3p agomir or negative control agomir (agomir-NC) on week 0, 2, 4, 6, 8, 10 after HFD feeding. MiR-377-3p was found to restore HFD-induced AS lesions and expressions of matrix metalloproteinase (MMP)-2, MMP-9, α-smooth muscle actin (α-actin) and calponin. In in vitro experiments, human VSMCs were tranfected with miR-377-3p agomir or agomir-NC, followed by treatment with oxidized low-density lipoprotein (ox-LDL). MiR-377-3p was observed to significantly inhibit ox-LDL-induced VSMC proliferation characterized by inhibited cell viability, expressions of proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E and cell cycle transition from G1 to S phase accompanied with less 5-Ethynyl-2'-deoxyuridine (EdU)-positive cells. Furthermore, MiR-377-3p significantly inhibited ox-LDL-induced VSMC migration characterized by inhibited wound closure and decreased relative VSMC migration. Besides, neuropilin2 (NRP2) was verified as a target of miR-377-3p. MiR-377-3p was observed to inhibit NRP2 expressions in vivo and in vitro. Moreover, miR-377-3p significantly inhibited MMP-2 and MMP-9 expressions in human VSMCs. Additionally, miR-377-3p-induced inhibition of VSMC proliferation and migration could be attenuated by NRP2 overexpression. These results indicated that miR-377-3p inhibited VSMC proliferation and migration via targeting NRP2. The present study provides an underlying mechanism for miR-377-3p-based AS therapy.
Soil erodibility (K-factor) is an essential factor in soil erosion prediction and conservation practises. The major obstacles to any accurate, large-scale soil erodibility estimation are the lack of ...necessary data on soil characteristics and the misuse of variable K-factor calculators. In this study, we assessed the performance of available erodibility estimators Universal Soil Loss Equation (USLE), Revised Universal Soil Loss Equation (RUSLE), Erosion Productivity Impact Calculator (EPIC) and the Geometric Mean Diameter based (Dg) model for different geographic regions based on the Chinese soil erodibility database (CSED). Results showed that previous estimators overestimated almost all K-values. Furthermore, only the USLE and Dg approaches could be directly and reliably applicable to black and loess soil regions. Based on the nonlinear best fitting techniques, we improved soil erodibility prediction by combining Dg and soil organic matter (SOM). The NSE, R2 and RE values were 0.94, 0.67 and 9.5% after calibrating the results independently; similar model performance was showed for the validation process. The results obtained via the proposed approach were more accurate that the former K-value predictions. Moreover, those improvements allowed us to effectively establish a regional soil erodibility map (1:250,000 scale) of water erosion areas in China. The mean K-value of Chinese water erosion regions was 0.0321(thah)·(haMJmm)−1 with a standard deviation of 0.0107(thah)·(haMJmm)−1; K-values present a decreasing trend from North to South in water erosion areas in China. The yield soil erodibility dataset also satisfactorily corresponded to former K-values from different scales (local, regional, and national).
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