PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.
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ABSTRACT:
PROVIDER: PRJNA542385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9043360_1.fastq.gz | Fastqsanger.gz | |||
| SRR9043360_2.fastq.gz | Fastqsanger.gz | |||
| SRR9043370_1.fastq.gz | Fastqsanger.gz | |||
| SRR9043370_2.fastq.gz | Fastqsanger.gz | |||
| SRR9043361_1.fastq.gz | Fastqsanger.gz |
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Project description:Cancer cells experience endoplasmic reticulum (ER) stress due to activated oncogenes and conditions of nutrient deprivation and hypoxia. The ensuing unfolded protein response (UPR) is executed by ATF6, IRE1 and PERK pathways. Adaptation to mild ER stress promotes tumor cell survival and aggressiveness. Unmitigated ER stress, however, will result in cell death and is a potential avenue for cancer therapies. Because of this yin-yang nature of ER stress, it is imperative that we fully understand the mechanisms and dynamics of the UPR and its contribution to the complexity of tumor biology. The PERK pathway inhibits global protein synthesis while allowing translation of specific mRNAs, such as the ATF4 transcription factor. Using thapsigargin and tunicamycin to induce acute ER stress, we identified the transcription factor C/EBPδ (CEBPD) as a mediator of PERK signaling to secretion of tumor promoting chemokines. In melanoma and breast cancer cell lines, PERK mediated early induction of C/EBPδ through ATF4-independent pathways that involved at least in part Janus kinases and the STAT3 transcription factor. Transcriptional profiling revealed that C/EBPδ contributed to 20% of thapsigargin response genes including chaperones, components of ER-associated degradation, and apoptosis inhibitors. In addition, C/EBPδ supported the expression of the chemokines CXCL8 (IL-8) and CCL20, which are known for their tumor promoting and immunosuppressive properties. With a paradigm of short-term exposure to thapsigargin, which was sufficient to trigger prolonged activation of the UPR in cancer cells, we found that conditioned media from such cells induced cytokine expression in myeloid cells. In addition, activation of the CXCL8 receptor CXCR1 during thapsigargin exposure supported subsequent sphere formation by cancer cells. Taken together, these investigations elucidated a novel mechanism of ER stress-induced transmissible signals in tumor cells that may be particularly relevant in the context of pharmacological interventions.
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Project description:Expression of the transcription factor CEBPD is induced at early stages of the endoplasmic reticulum (ER) stress response. In order to identify the genes modulated by CEBPD during the ER stress response, we transiently silenced CEBPD expression in MDA-MB-435 melanoma cells and isolated mRNA at 6 h of treatment with Thapsigargin or DMSO control. As control, cells were transfected with two different control siRNA oligonucleotides. Results provide insights into which genes are modulated by CEBPD and/or Thapsigargin in MDA-MB-435 cell
2021-11-01 | GSE131048 | GEO
Project description:The spleen, as the prominent site for extramedullary myelopoiesis in cancer, generates significant amounts of myeloid cells to promote tumor progression. Cancer-associated splenic myelopoiesis is mediated by a population of functionally distinct hematopoietic stem/progenitor cells (HSPCs) that are committed to immunosuppressive myeloid cell generation, but the molecular mechanism regulating this response remains unclear. Here, we found that HSPCs in the spleen of tumor-bearing mice exhibited accelerated protein synthesis and engaged in a robust endoplasmic reticulum (ER) stress response. Single-cell RNA sequencing showed that the ER stress response was concomitant with the myeloid-biased lineage commitment and dysfunction of HSPCs in the spleen. PKR-like ER resident kinase (PERK), a molecular sensor of ER stress, directed HSPC differentiation into myeloid-derived suppressor cells (MDSCs) via PERK–eIF2α–ATF4–C/EBPβ signaling. Inhibition of this signaling prevented the emergence of granulocyte/macrophage colony-stimulating factor-expressing HSPCs in the spleen and disrupted the positive feedback-driven splenic myelopoiesis. Consequently, a blockade of PERK abated the suppressive function of tumor-infiltrating MDSCs and increased cytotoxic T cell infiltration, reshaping the tumor microenvironment to effectively suppress disease progression and potentiate both immuno- and targeted therapies. In accordance, activation of PERK–ATF4–C/EBPβ signaling was indispensable for the differentiation of human umbilical cord blood-derived HSPCs into functionally competent MDSCs. Together, these results indicate a crucial role for the cellular ER stress sensor PERK in modulating splenic HSPC activities in cancer, suggesting novel therapeutic opportunities for targeting the tumor-promoting myeloid response at its source. Raw data are available on Genome Sequence Archive, Bioproject accession number: PRJCA003519
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Project description:We examined if pediatric AMLs rank-ordered according to C/EBPδ expression showed the activation of similar pathways. AML samples were dichotomized into groups including the upper quartile (Q1) and the lower three quartiles (Q2-4) according to their C/EBPδ expression values. Moreover, AML samples were associated to French-American-British (FAB) classification.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a horrid disease with a terrifyingly low 5- year survival rate of only 12%. While this rate has slightly increased over the past decade, the incidence of PDAC has risen faster, by about 1% every year. Pre-clinical models are being employed with the aim to better understand the underlying tumor biology but sadly, a translation into the clinic often fails due to unforeseen complications. In a previous study, we showed that the transcription factor C/EBPδ has tumor-suppressive effects on PDAC cells in vitro. In this study, we take those findings a step further and assess the effect of C/EBPδ in a preclinical PDAC model in mice. We establish that the lack of oxygen in vivo – hypoxia - counteracts the tumor-suppressive effects of C/EBPδ in PDAC cells and suggest that this is partly mediated by a reciprocal feedback loop between C/EBPδ and HIF-1α. Although RNA-sequencing shows that the tumor-suppressive effects of C/EBPδ are not entirely abrogated under hypoxia, our study demonstrates the importance of considering major physiological parameters in order to make clinically relevant propositions.
2024-09-18 | GSE226038 | GEO
Project description:The UPR (Unfolded Protein Response) is a well-orchestrated response to ER protein folding and processing overload, integrating both transcriptional and translational outputs. Its three arms in mammalian cells, the PERK translational response arm, together with the ATF6 and IRE1-mediated transcriptional arms, have been thoroughly investigated. Using ribosome footprint profiling, we performed a deep characterization of the gene expression programs involved in the acute and adaptive ER stress responses. We utilized MEFs (Mouse Embryonic Fibroblasts) treated with Thapsigargin for different durations, that were wither WT or PERK knockouts, to determine the role of PERK in the acute and chronic UPR. We characterized three major gene expression programs: acute induction, chronic induction, and repression, and found that they were all PERK dependent. All three programs were recapitulated in publicly available data and in NIH3T3 cells. While PERK -/- cells did not recapitulate these responses in the acute timepoints, late timepoints showed an extremely weak induction/repression, suggesting that the chronic responses in WT cells are largely PERK dependent as well. We found that most ER target proteins were significantly repressed; including transmembrane proteins, glycoproteins, and proteins with disulfide bonds. We further demonstrate the downregulation of cyclins, while the expression of the amino acid biosynthesis pathway was enhanced.
2019-03-20 | GSE118660 | GEO
Project description:Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of the common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the key enzymes in their production, may hold the key to the treatment of pre- and post-term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ) is such a transcription factor which underlies the feed-forward induction of COX-2 and 11β-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδ in amnion increases along with COX-2 and 11β-HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδ may serve as a novel pharmaceutical target in the amnion for treatment of pre- and post-term labor.
2021-07-15 | GSE166320 | GEO
Project description:Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of the common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the key enzymes in their production, may hold the key to the treatment of pre- and post-term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ)is such a transcription factor which underlies the feed-forward induction of COX-2 and 11β-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδin amnion increases along with COX-2 and 11β-HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδmay serve as a novel pharmaceutical target in the amnion for treatment of pre- and post-term labor.
2021-07-15 | GSE166454 | GEO
Project description:Amnion-derived prostaglandin E2 (PGE2) and cortisol are key to labor onset. Identification of the common transcription factor driving the expression of both cyclooxygenase-2 (COX-2) and 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), the key enzymes in their production, may hold the key to the treatment of pre- and post-term labor. Here, we have found that the CCAAT enhancer binding protein δ (C/EBPδ) is such a transcription factor which underlies the feed-forward induction of COX-2 and 11β-HSD1 expression by their own products PGE2 and cortisol in human amnion fibroblasts so that their production would be ensured in the amnion for the onset of labor. Moreover, the abundance of C/EBPδ in amnion increases along with COX-2 and 11β-HSD1 at term and further increases at parturition. Knockout of C/EBPδ in mice delays the onset of labor further supporting the concept. In conclusion, C/EBPδ may serve as a novel pharmaceutical target in the amnion for treatment of pre- and post-term labor.
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Project description:To identify the target genes of integrated stress reponse (ISR), we have employed whole genome microarray expression in MEF cells. ISR gene setimation under ER stress condition using Perk -/-, Atf4 -/-, eIF2a S51A mutant, Fv2E-PERK MEF cells
2015-09-01 | E-GEOD-49598 | biostudies-arrayexpress