Endocrine cell ER stress conservation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA997368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR25388034_1.fastq.gz | Fastqsanger.gz | |||
| SRR25388034_2.fastq.gz | Fastqsanger.gz | |||
| SRR25388035_1.fastq.gz | Fastqsanger.gz | |||
| SRR25388035_2.fastq.gz | Fastqsanger.gz |
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Project description:Endocrine cells are dedicated to the production and processing of hormones, from peptides to small molecules, to regulate key physiological processes including glucose homeostasis and metabolism. Because of this relatively high productivity, endocrine cells must handle a variety of stresses from oxidative stress to the unfolded protein response of the endoplasmic reticulum (UPRER). While much is known about the major pathways regulating the UPRER, the roles of endocrine cell type-specific, context-dependent, and time-dependent transcriptional changes are not well explored. To identify unique and shared responses to the UPRER across a subset of endocrine cell types, we tested representative lines for β-cells (insulin), α-cells (glucagon), δ-cells (somatostatin), X/A-cells (ghrelin), L-cells (glucagon-like peptide 1 (GLP1)), and thyrotropes (thyroid hormone and thyroglobulin). We exposed each cell type to the canonical ER stressor thapsigargin for 6 and 24 h, or vehicle (DMSO 0.1%) for 24 h and performed mRNA sequencing. Analysis of the data showed all lines responded to thapsigargin. Comparisons of up- and down-regulated genes between each line revealed both shared and unique transcriptional signatures. These data represent a valuable mineable set of candidate genes which may have cell type-specific functions during the UPRER, and have the potential to lead to new understanding about how different endocrine cells mitigate or succumb to ER stress.
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Project description:Transient ER stress cell-autonomously promotes beta cell cycling
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Project description:While estrogen receptor positive breast tumors generally respond well to endocrine therapy (ET), up to 40% of patients will experience relapse, either while on endocrine therapy or after ET is completed. We have previously shown that the selective pressure of tamoxifen activates the pro-survival NFkB pathway in patient tumors, breast cancer cell lines, and breast cancer xenograft tumors, and that this activation allows for survival of a population of ET-tolerant cells, which can contribute to relapse after ET withdrawal. Here, we utilized single cell RNA-sequencing to characterize survival pathways in NFkB+, ET-tolerant cells and identified activation of the integrated stress response as a critical survival mechanism. Moreover, we found key players in this pathway are regulated by ET in patient derived organoids. In addition, we developed an ET-tolerant gene signature that can be found in metastatic cell populations and that predicts poor outcome to ET. Our findings suggest that co-targeting of ER and key players in the integrated stress response may be a viable therapeutic strategy to eliminate cells that survive the selective pressure of ET.
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Project description:The majority of breast cancers (BCs) harboring estrogen receptor (ER) have shown endocrine resistance. Our previous study has demonstrated that ferredoxin reductase (FDXR) promotes mitochondrial function and ER+ breast tumorigenesis. Here, integrative analyses of targeted metabolomics assay and gene expression profiling show that FDXR potentiates fatty acid oxidation (FAO) through positive regulation of carnitine palmitoyltransferase 1A (CPT1A) expression. Treatment with ER antagonist (tamoxifen) or degrader (fulvestrant) leads to increased expression of FDXR and CPT1A. In line with this finding, we find that FDXR-CPT1A-FAO axis is required for primary and endocrine resistant breast cancer cell growth. Therapeutically,combining endocrine therapy with FAO inhibitor synergistically reduces primary and endocrine resistant breast cancer cell growth, thus providing a potential combinatory treatment for ER+ breast cancer. We used microarrays to be able to elucidate to some extent the gene regulatory mechanisms of FDXR regulating breast cancer metabolism.
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Project description:Endocrine therapy in combination with CDK4/6 inhibition doubles the progression-free survival of patients with advanced ER+ breast cancer, but resistance is inevitable, leaving patients with limited treatment options. Here, we performed unbiased genome-wide CRISPR/Cas9 knockout screens using ER+ breast cancer cells to identify novel drivers of resistance to combination endocrine therapy (tamoxifen) and CDK4/6 inhibitor (palbociclib) treatment. Our screens identified the inactivation of JNK signalling, including loss of the kinase MAP2K7, as a key driver of combination resistance. We developed multiple CRISPR/Cas9 knockout ER+ breast cancer cell lines (MCF-7 and T-47D) to investigate the effects of MAP2K7 and downstream MAPK8 and MAPK9 loss. MAP2K7 knockout increased metastatic burden in vivo and led to impaired JNK-mediated stress responses, as well as promoting cell survival and reducing senescence entry following endocrine therapy and CDK4/6 inhibitor treatment. Mechanistically, this occurred via loss of the AP-1 transcription factor c-JUN, leading to an attenuated response to combination endocrine therapy plus CDK4/6 inhibition. Furthermore, we analysed ER+ advanced breast cancer patient cohorts and found that inactivation of the JNK pathway was associated with increased metastatic burden, and low pJNKT183/Y185 activity correlated with a poorer response to systemic endocrine and CDK4/6 inhibitor therapies. Overall, we demonstrate that suppression of JNK signalling enables persistent growth during combined endocrine therapy and CDK4/6 inhibition. Our data provide a pre-clinical rationale to screen patients’ tumours for JNK signalling deficiency prior to receiving combined endocrine therapy and CDK4/6 inhibition.
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Project description:In previous studies, we showed that Tet2 controls the responses of beta cells to inflammation in a model of autoimmune Type 1 diabetes, but the specific cell types affected by Tet2 loss in islets was not clear and the molecular mechanisms responsible for the autoimmune responses and beta cell death were unknown. We found that Tet2-deficient islets have fewer islet infiltrating lymphocytes beginning 8-10 weeks after bone marrow transplant, reduced activation of CD8+ T cells, and greater CD8+ T cell repertoire diversity. Transcription factor finding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To confirm the effects of TET2 in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2(TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.
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Project description:In previous studies, we showed that Tet2 controls the responses of beta cells to inflammation in a model of autoimmune Type 1 diabetes, but the specific cell types affected by Tet2 loss in islets was not clear and the molecular mechanisms responsible for the autoimmune responses and beta cell death were unknown. We found that Tet2-deficient islets have fewer islet infiltrating lymphocytes beginning 8-10 weeks after bone marrow transplant, reduced activation of CD8+ T cells, and greater CD8+ T cell repertoire diversity. Transcription factor finding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To confirm the effects of TET2 in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2(TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.
2026-01-05 | GSE305093 | GEO
Project description:In previous studies, we showed that Tet2 controls the responses of beta cells to inflammation in a model of autoimmune Type 1 diabetes, but the specific cell types affected by Tet2 loss in islets was not clear and the molecular mechanisms responsible for the autoimmune responses and beta cell death were unknown. We found that Tet2-deficient islets have fewer islet infiltrating lymphocytes beginning 8-10 weeks after bone marrow transplant, reduced activation of CD8+ T cells, and greater CD8+ T cell repertoire diversity. Transcription factor finding motifs for interferon responses factors and inflammatory signaling molecules were enriched in Tet2-responsive cis-regulatory elements across all KO islet endocrine cells, but we observed beta cell-specific enrichment of TFs modulating homeostatic or ER stress response pathways. To confirm the effects of TET2 in human islets, we induced ER stress with brefeldin A or thapsigargin and inhibited TET2 with Bobcat 339. Pharmacologic TET inhibition reduced expression of ER stress response genes, inflammatory responses, and stress-induced beta cell death. We conclude that Tet2(TET2) can regulate ER stress responses involved in beta cell killing in autoimmune/inflammatory settings.
2026-01-05 | GSE305092 | GEO