Dysregulation of transcription factor activity during formation of cancer associated fibroblasts.
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ABSTRACT:
PROVIDER: PRJNA669052 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12820300_1.fastq.gz | Fastqsanger.gz | |||
| SRR12820300_2.fastq.gz | Fastqsanger.gz | |||
| SRR12820301_1.fastq.gz | Fastqsanger.gz | |||
| SRR12820301_2.fastq.gz | Fastqsanger.gz | |||
| SRR12820302_1.fastq.gz | Fastqsanger.gz |
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Project description:Introduction: The reciprocal interactions between cancer cells and the CAFs serve an important role in cancer progression. Those feedback loops depend on tumor developmental stage and the tissue microenvironment and may promote different CAFs subpopulations in different types of malignancy. Here, we investigated the activation of transcription factors (TFs) in cocultures of fibroblasts with normal prostate or tumorous cells with mRNA sequencing. Materials and Methods: Coculture of WPMY-1 (normal prostate fibroblasts) with RWPE-1 (normal prostate epithelial cells) or RWPE-2 (cancer prostate epithelial cells) were done using transwell inserts. As a control, we used WPMY-1 culture alone. After 6h and 24h of coculture, we performed mRNA-sequencing., We used SEPIRA (Systems EPigenomics Inference of Regulatory Activity) package and mRNA-seq data of 483 cultured fibroblasts from GTEx to calculate the TFs activity score from mRNA-seq expression in our samples. Results: We determined changes in TFs activity between time points in each group. We found 5 TFs (RUFY3, SCMH1, NFIX, ZBTB25, NFE2L1), that increase activity between 6h and 24h in each condition (control, coculture with RWPE1 and coculture with RWPE2). Only one TF (RNF4) increased activity in RWPE-1 coculture, while dysregulation of 45 TFs (7 decreased activity and 38 increased activity) was observed in coculture with RWPE-2. Pathway analysis showed that these 45 dysregulated TFs in fibroblasts after coculture with RWPE2 cells may be associated with RUNX1 and PTEN pathways. Conclusion: Our results demonstrate that CAFs transformation can be orchestrated by dysregulation of multiple TFs, therefore may suggest multiple signaling pathways that participate in CAFs transformation. Moreover, we show potential pathways, that could be involved in feedback loop between fibroblast and epithelial cells in tumors.
2020-12-07 | GSE159493 | GEO
Project description:The reciprocal interactions between cancer cells and the quiescent fibroblasts leading to the activation of cancer-associated fibroblasts (CAFs) serve an important role in cancer progression. Here, we investigated the activation of transcription factors (TFs) in prostate fibroblasts (WPMY cell line) co-cultured with normal prostate or tumorous cells (RWPE1 and RWPE2 cell lines, respectively). After indirect co-cultures, we performed mRNA-seq and predicted TF activity using mRNA expression profiles with the Systems EPigenomics Inference of Regulatory Activity (SEPIRA) package and the GTEx and mRNA-seq data of 483 cultured fibroblasts. The initial differential expression analysis between time points and experimental conditions showed that co-culture with normal epithelial cells mainly promotes an inflammatory response in fibroblasts, whereas with the cancerous epithelial, it stimulates transformation by changing the expression of the genes associated with microfilaments. TF activity analysis revealed only one positively regulated TF in the RWPE1 co-culture alone, while we observed dysregulation of 45 TFs (7 decreased activity and 38 increased activity) uniquely in co-culture with RWPE2. Pathway analysis showed that these 45 dysregulated TFs in fibroblasts co-cultured with RWPE2 cells may be associated with the RUNX1 and PTEN pathways. Moreover, we showed that observed dysregulation could be associated with FER1L4 expression. We conclude that phenotypic changes in fibroblast responses to co-culturing with cancer epithelium result from orchestrated dysregulation of signaling pathways that favor their transformation and motility rather than proinflammatory status. This dysregulation can be observed both at the TF and transcriptome levels.
| S-EPMC7699520 | biostudies-literature
Project description:Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole. mRNAs were analyzed by two color microarray from two separate human neonatal dermal fibroblasts cell lines in proliferating, 7 days contact inhibition, or 14 days contact inhibition. Contact inhibited samples were co-hybridized to proliferating samples as a control, while an additional array co-hybridized the two proliferating samples to analyze reproducibility.
2012-11-30 | E-GEOD-42612 | biostudies-arrayexpress
Project description:Many cells in mammals exist in the state of quiescence, which is characterized by reversible exit from the cell cycle. Quiescent cells are widely reported to exhibit reduced size, nucleotide synthesis, and metabolic activity. Much lower glycolytic rates have been reported in quiescent compared with proliferating lymphocytes. In contrast, we show here that primary human fibroblasts continue to exhibit high metabolic rates when induced into quiescence via contact inhibition. By monitoring isotope labeling through metabolic pathways and quantitatively identifying fluxes from the data, we show that contact-inhibited fibroblasts utilize glucose in all branches of central carbon metabolism at rates similar to those of proliferating cells, with greater overflow flux from the pentose phosphate pathway back to glycolysis. Inhibition of the pentose phosphate pathway resulted in apoptosis preferentially in quiescent fibroblasts. By feeding the cells labeled glutamine, we also detected a “backwards” flux in the tricarboxylic acid cycle from α-ketoglutarate to citrate that was enhanced in contact-inhibited fibroblasts; this flux likely contributes to shuttling of NADPH from the mitochondrion to cytosol for redox defense or fatty acid synthesis. The high metabolic activity of the fibroblasts was directed in part toward breakdown and resynthesis of protein and lipid, and in part toward excretion of extracellular matrix proteins. Thus, reduced metabolic activity is not a hallmark of the quiescent state. Quiescent fibroblasts, relieved of the biosynthetic requirements associated with generating progeny, direct their metabolic activity to preservation of self integrity and alternative functions beneficial to the organism as a whole.
2012-11-30 | GSE42612 | GEO
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