Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A tumor microenvironment-driven network regulated by STAT3 and p65 controls the enrichment of cancer stem cells in human HR+/HER2- breast cancer cells

ABSTRACT: The high incidence of the HR+/HER2- breast cancer subtype is a major public health concern, leading us to explore the way three arms of the tumor microenvironment (TME) – hormonal, inflammatory and growth-stimulating – affect tumor progression in this disease. Our past findings indicate that such a joint “TME Stimulation” induces pro-metastatic traits in HR+/HER2- cells, primarily enrichment of cancer stem cells (CSCs), playing key roles in metastasis in vivo. Here, we reveal unexpected roles for STAT3 in this setting, serving as negative regulator that limits CSC enrichment while promoting cancer cell abilities to exploit the immune/inflammatory system in their favor. Moreover, our data provide evidence to novel roles for the strong pro-inflammatory transcription factor p65, whose activities could compensate for complete loss of STAT3 and recapitulate its ability to limit CSC enrichment. These findings call for in depth studies on STAT3 and p65 roles in regulating TME activities in malignant diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226339 | GEO | 2023/04/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling

Project description:Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem-cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with Transforming Growth Factor-β (TGF-β)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA-binding, and induced SMAD3-dependent transcriptional activity. Suppression of TGF-β receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that, targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence.

2016-12-13 | GSE92297 | GEO

C-terminally phosphorylated p27 regulates STAT3 transcriptional activation, inducing gene programs driving mammary duct and cancer stem cell expansion

Project description:While, p27 inhibits cell cycle in normal cells, in most cancers, p27 acquires oncogenic activities when phosphorylated by PI3K-activated kinases at T157 and T198 (p27pTpT). Mechanistically, these oncogenic functions of p27pTpT are poorly understood. Here, we show that p27pTpT promotes cancer stem cell (CSC) expansion through STAT3 both in vitro and in vivo. p27 phosphorylation increased STAT3 recruitment to chromatin to induce CSC self-renewal genes including MYC, the Notch ligand, JAG1, and ANGPTL4. We identify a feed-forward loop in which p27pTpT/STAT3 co-represses the Pyk2 inhibitor, PTPN12. Pyk2 in turn activates STAT3, driving CSCs expansion. p27pTpT is also shown to critically regulate mammary gland development. Mammary transgenic expression of phosphomimetic, cyclin-CDK binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis and hyperplasia, yielding primary and metastatic breast cancers. This supports a model in which p27pTpT co-regulates STAT3 to drive programs governing stem cell expansion or maintenance in normal and cancer tissues.

2024-04-19 | GSE233351 | GEO

RNA sequencing of NF-kB knockout (KO) U937 cells

Project description:Transcription factors of NF-kB family play central roles in inflammatory responses. However, most of our current understanding on these factors are based on in vitro context specific studies and animal models, and human specific cellular and pathophysiological functions at molecular level are poorly understood. Here, we have designed a new oligomer based lentiviral pgRNAs-CRISPR-Cas9 knock-out (KO) approach and performed RNA-seq on 11 independent clones representing p50, p52, p65, c-REL and RELB KO cells to systematically study NF-kB family of transcription factors in monocytic cells U937, in steady and inflammatory state. Our analysis reveals factor-specific and common genes and pathways that are dysregulated in an inflammatory state. However, in a steady state respective KO clones showed specific transcriptional perturbations. Incorporating DNA-binding ChIP-ChIP information in the transcriptomic data uncovered enrichment of metabolic and leukemia associated pathways in p65-/- cells. Using acute myeloid leukemia (AML) patient’s data, metabolic, proliferation and xenograft models we showed an anti-leukemic functions of p65 which was mediated by metabolic plasticity and stemness.

2020-10-26 | GSE153158 | GEO

Macrophages induce inflammation by efferocytosis of apoptotic prostate cancer cells via HIF-1α stabilization

Project description:Clearance of apoptotic cancer cells by macrophages, known as efferocytosis, fuels the bone-metastatic growth of prostate cancer cells via pro-inflammatory and immunosuppressive mechanisms that are still unclear. In this study, single-cell transcriptomics of bone marrow macrophages undergoing efferocytosis of apoptotic prostate cancer cells revealed a significant enrichment of a cellular response to hypoxia. Here we show that efferocytic macrophages promote HIF-1α stabilization under normoxic conditions through interaction with phosphorylated STAT3. Inflammatory cytokine gene expression analysis of efferocytic HIF-1α-mutant macrophages revealed a reduced expression of the pro-tumorigenic Mif. Furthermore, stabilization of HIF-1α using the HIF-prolyl-hydroxylase inhibitor, Roxadustat, enhanced MIF expression in macrophages. Finally, macrophages treated with recombinant MIF protein activated NF-κB (p65) signaling increased the expression of pro-inflammatory cytokines. Altogether, these findings suggest that the clearance of apoptotic cancer cell by tumor-associated macrophages triggers p-STAT3/HIF-1α/MIF signaling to enhance tumor-promoting inflammation in bone, suggesting this axis as a target for metastatic prostate cancer.

2022-12-14 | GSE180638 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive organoids derived from patient derived xenografts from patients who progressed on palbociclib

Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.

2023-07-10 | GSE229146 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive breast cancer cell lines: MCF-7 and T47D

2023-07-10 | GSE222367 | GEO

Mouse livers during pneumonia

Project description:This SuperSeries is composed of the following subset Series: GSE32105: Expression data from mouse livers lacking STAT3 and RelA during pneumonia GSE35513: Expression data from mouse livers lacking NF-kappaB RelA (p65) during pneumonia GSE35514: Expression data from mouse livers lacking STAT3 during pneumonia GSE35515: Expression data from mouse livers expressing or lacking Cre recombinase during pneumonia Refer to individual Series

2012-02-16 | E-GEOD-35516 | biostudies-arrayexpress

Inhibition of the autocrine loop IL6-JAK2-STAT3-Calprotectin as targeted therapy for HR-/HER2+ breast cancers

Project description:Inhibition of the autocrine loop IL6-JAK2-STAT3-Calprotectin as targeted therapy for HR-/HER2+ breast cancers

| PRJNA263583 | ENA

Entinostat decreases immune suppression to promote an anti-tumor response within a HER2+ breast tumor microenvironment.

Project description:Therapeutic combinations to alter solid tumor microenvironments (TME) in immunosuppressive tumors such as breast cancer are essential to improve their responses to immune checkpoint inhibitors (ICIs). Entinostat, an oral histone deacetylase inhibitor (HDACi), has been shown to improve responses to ICIs in various tumor models with immunosuppressive TMEs. The precise and comprehensive alterations to the TME induced by entinostat remain unknown. Here, we employ single-cell RNA-sequencing on HER2 overexpressing breast tumors from mice treated with entinostat and ICIs to characterize for the first time changes across all cell types within the TME. This analysis demonstrates that treatment with entinostat induces a shift from a pro-tumor to an anti-tumor TME signature characterized predominantly by changes in the myeloid cells. We confirm myeloid-derived suppressor cells (MDSCs) within entinostat-treated tumors are associated with a less suppressive G-MDSC phenotype and now demonstrate altered suppressive signaling involves the NFkB and STAT3 pathways. In addition to MDSCs, tumor-associated macrophages are epigenetically reprogrammed toward an anti-tumor M1-like phenotype likely contributing to a more sensitized TME. Overall, our in-depth analysis suggests entinostat-induced changes on multiple myeloid cell types reduce immunosuppression and increase mechanisms of an anti-tumor response that improve sensitivity to ICI. Sensitization of the TME by entinostat could ultimately broaden the population of patients with breast cancer who could derive benefit from ICIs.

2022-01-18 | GSE166321 | GEO

Crosstalk between the STAT3, NF-kB and Notch signaling pathways in glioblastoma stem cells

Project description:In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. We demonstrate that adherent glioma CSCs exhibit characteristics previously described for CSCs grown in suspension culture. The expression of CD133, Sox2 and Nestin increased when compared to glioma cells grown in monolayer, and the adherent CSCs were ~100 times more tumorigenic in vivo than monolayer cultured glioma cells. We also found that while the STAT3 and NF-κB signaling pathways are constitutively activated in glioma lines, these pathways are dramatically activated in glioma CSCs. Treatment with STAT3 inhibitors led to a loss of nuclear activation of STAT3 signaling and suppression of growth in both monolayer and CSC conditions. There was a markedly greater growth suppressive effect on glioma CSCs, suggesting that targeted therapy of these key pathways in glioma CSCs may be possible. To further investigate potential biomarkers in glioma CSCs, microarray analysis was performed and revealed deregulation of the Notch signaling pathway. This constitutive activation of STAT3, NF-κB, and Notch pathways in glioma CSCs helps identify novel therapeutic targets for the treatment of glioma. GBM6 cells were continuously maintained as subcutaneous xenografts in NSG mice, and monolayer and CSC cultures were derived from freshly harvested tumor tissue. A total of 6 samples were subjected to microarray analysis, with three biological replicates for each experimental condition.

2013-06-19 | E-GEOD-48079 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data