Breast tumors interfere with endothelial TRAIL at the pre-metastatic niche to promote cancer cell seeding
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ABSTRACT:
PROVIDER: PRJNA820033 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: To study the effects of endothelial cell (EC)-specific TRAIL depletion on lung endothelial cells. Here, we used RNA sequencing to explore the transcriptional changes of lung ECs upon deletion of TRAIL specifically in ECs. RNA from 2.000.000 sorted lung ECs (viability dye- CD45- CD31+) from EC-specific TRAIL WT and KO mice (Cdh5.iCreERT2xTnfsf10Lox/Lox) were isolated and the concentration as well as purity was determined spectrophotometrically using the Nanodrop ND-1000 (Nanodrop Technologies). Per sample, an amount of 3000ng of total RNA was used as input. Subsequently, preparation was performed with KAPA stranded mRNA seq according to the protocol and samples were pooled equimolar. Sequencing was performed as single end of 50bp on hiseq 4000 from Illumina. 35-40 Million reads were generated per sample. Raw FASTQ reads were mapped using STAR v2.7.1a and gene reads counts were estimated by RSEM v1.2.28 using GENCODE reference annotation of the mouse genome (GRCm38), version M24 (Ensembl 99). Gene reads counts were estimated by RSEM using GENCODE reference annotation of the mouse genome (GRCm38), version M24 (Ensembl 99). Differential expression of EC-specific TRAIL KO (EC-Tg/W) vs control (EC-W/W) was performed using the DESeq2 R package (v1.26.0). The significance was determined by padj < 0,05. The gene set enrichment analysis (GSEA) was performed using the pre-ranked gene list by log2 fold-change (EC-Tg/W vs EC-W/W control) and the MSigDB gene sets. Only gene sets containing between 5 and 500 genes were retained and the number of permutations was set at 1000.
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2006-01-01 | E-MEXP-247 | biostudies-arrayexpress
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Project description:Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors.
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Project description:Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as a defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting numerous tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome supports cell transformation, we asked whether factor(s) of this secretome would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pre-transformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling analysis of CMS-exposed pre-transformed cells revealed paracrine autoregulatory loop of senescence-associated secretome factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with MYC upregulation and massive changes in gene regulation. CMS-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL, thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL sensitizing effect on pre-transformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) may provide a mechanistic insight in the acquisition of TRAIL sensitivity and lead to novel concepts for the apoptogenic therapy of pre-malignant and TRAIL-resistant tumors. Pre-transformed BJEL cells were incubated with CMS for 0, 1, 3, 6, 8, 16 or 24 h respectively. Total RNA has been extracted from each time point and used for gene expression analysis (Affymetrix Human Gene 1.0 ST Arrays).
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