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IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scATAC-seq]

ABSTRACT: IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scATAC-seq]

PROVIDER: PRJNA988486 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25057240_1.fastq.gz	Fastqsanger.gz
	SRR25057240_2.fastq.gz	Fastqsanger.gz
	SRR25057241_1.fastq.gz	Fastqsanger.gz
	SRR25057241_2.fastq.gz	Fastqsanger.gz

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IL6/STAT3 co-opts ER regulatory elements to drive metastasis in breast cancer

Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. By integrating pre-clinical models and clinical specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancer-elements shared with ER and its pioneer factor FOXA1. Although IL6 activated STAT3 and ER/FOXA1 share cis-regulatory regions, STAT3 drives transcription independent of ER and FOXA1 function, and the IL6/STAT3 gene program is not influenced by ER-targeted therapies, decoupling these two important pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but independent actionable pathways controlling breast cancer progression.

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Increased risk of mammary cancer recurrence in socially isolated rats is linked to upregulation of IL6/JAK/STAT3 and inhibition of oxidative phosphorylation signaling, activities blocked by the herbal mixture Jaeumganghwa-tang

Project description:While multifactorial in origin, one of the most prevalent and impactful consequences of social isolation is an increase in cancer mortality. Using a preclinical model in Sprague Dawley rats, we found that social isolation increased the risk of mammary tumor recurrence after completion of antiestrogen therapy. The increased recurrence risk was associated with an upregulation of IL6/JAK/STAT3 signaling in the mammary glands and tumors and suppression of mitochondrial oxidative phosphorylation (OXPHOS) pathway. Also inhibited were genes involved in mitochondrial pyruvate transport and the conversion of pyruvate to acetyl CoA but lactate levels were not altered. In addition, social isolation increased the expression of receptor for advanced glycation end-products (RAGE), consistent with the impaired insulin sensitivity and weight gain linked to social isolation. All these changes are commonly associated with aging. In socially isolated animals consumption of the anti-inflammatory 12 herb mixture Jaeumganghwa-tang (JGT) inhibited IL6/JAK/STAT3 signaling, upregulated OXPHOS signaling, suppressed expression of the RAGE ligands S100a8 and S100a9, and prevented the increased risk of mammary cancer recurrence. In summary, increased breast cancer mortality among socially isolated survivors may be most effectively prevented by focusing on the period following the completion of endocrine therapy using tools that inhibit IL6/JAK/STAT3 inflammatory cytokine signaling and reverse disrupted OXPHOS.

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Hepatocyte CD44 drives IL6/STAT3-high neighborhoods linked to blunted T-cell effector function in the aged liver

Project description:Liver cancer incidences increase beyond 55 years of age suggesting that molecular, cellular and tissue changes accompanying aging contribute critically to tumor initiation. However, the mechanisms linking aging and liver cancer initiation are not well understood. Our study investigates the role of CD44, a transmembrane glycoprotein and a known marker of tumor-initiating cells (TICs), in age-associated liver pathophysiology. Aged livers showed an accumulation of CD44 expressing hepatocytes. Single nucleus RNA sequencing revealed that CD44 expressing hepatocytes in aged livers exhibit enrichment of immune modulatory genes and activation of the IL6/JAK/Stat3 pathway. Spatial analyses confirmed upregulation of the IL6/JAK/Stat3 pathway and showed that CD44-expressing hepatocytes are proximal to T-cell neighborhoods exhibiting reduced cytokine expression. In adoptive transfer assays, ex vivo-activated CD8+ T cells mounted a lower antigen-specific IFNg response in aged livers than in young liver, consistent with an immune suppressive aged milieu. Hepatocyte-specific loss of Cd44 expression in aged livers compromised IL6/JAK/Stat3 activity and other immune/fibrotic gene signatures, supporting a contribution of hepatocyte Cd44 to age-associated immune dysregulation and early fibrosis. Our findings identify an aging-associated hepatocyte CD44 state with IL6/JAK/Stat3 activation, blunted T cell effector signals and early fibrotic cues.

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IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scATAC-seq]

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Project description:The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein found that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induced EMT and migration in vitro and metastasis in vivo, which were suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secreted a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution.

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IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer [ATAC-Seq]

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IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (ChIP-Seq)

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IL6-STAT3 downstream targets in MCF10A/MCF10A.ErbB2* cells

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IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression.

Project description:IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression.

| PRJNA988480 | ENA

IL6/STAT3 co-opts ER/FOXA1 regulatory elements to drive metastasis in breast cancer (RNA-Seq)

Project description:Interleukin 6 (IL6) signaling has been associated with an aggressive and metastatic phenotype in multiple solid tumors including breast cancer, but its mechanism of action in mediating tumor progression and treatment response is not clear. By exploiting a clinically relevant intraductal xenograft model of estrogen receptor a positive (ER+) breast cancer, we demonstrate that IL6 increases both primary tumor growth and distant metastases. In pre-clinical models and clinical specimens, signal transducer and activator of transcription 3 (STAT3) mediates IL6-induced activation of a metastatic gene program from enhancers shared with ER and its pioneer factor FOXA1. However, STAT3 drives transcription independent of ER and FOXA1 function from these enhancers, and the IL6/STAT3 pathway is therefore resistant to ER-targeted therapies, decoupling these two important oncogenic pathways. This demonstrates that ER/FOXA1 and IL6/STAT3 are two parallel, but functionally independent and actionable pathways controlling breast cancer progression.

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