Fibroblast growth factor 21 ameliorates cholestatic liver injury via a hepatic FGFR4-JNK pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1005176 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25628832_1.fastq.gz | Fastqsanger.gz | |||
| SRR25628832_2.fastq.gz | Fastqsanger.gz | |||
| SRR25628833_1.fastq.gz | Fastqsanger.gz | |||
| SRR25628833_2.fastq.gz | Fastqsanger.gz | |||
| SRR25628834_1.fastq.gz | Fastqsanger.gz |
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Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
2023-08-19 | GSE240733 | GEO
Project description:Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival. However, some HER2+ patients (~15%) still develop drug resistance after receiving trastuzumab treatment, leading to treatment failure. Using CCLE and METABRIC database analyses, we found that fibroblast growth factor receptor 4 (FGFR4) mRNA was highly detected in tumors from HER2+ breast cancer patients (P<0.001) and was associated with poorer survival in breast cancer patients. Through retrospective immunohistochemical staining analysis, we detected higher expression of FGFR4 protein in breast cancer tissues collected from patients who were resistant to trastuzumab therapy compared with breast cancer patients who responded to treatment. An FGFR4 inhibitor (FGF401) effectively inhibits tumor growth in trastuzumab-insensitive patient-derived xenograft (PDX) tumor-bearing mice. For molecular mechanism studies, we demonstrated that HER2/FGFR4 protein complexes were detected on the cell membrane of the tumor tissues in these trastuzumab-insensitive PDX tumor tissues. After trastuzumab treatment in these drug-resistant breast cancer cells, FGFR4 translocates and enters the nucleus. However, trastuzumab-induced nuclear translocation of FGFR4/HER2-intracellular domain protein complex in trastuzumab-resistant cancer cells is blocked by FGF401 treatment. We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.
2024-11-08 | GSE262860 | GEO
Project description:Advanced ovarian cancer is the most lethal gynecologic malignancy in the United States. Currently patients are treated by surgical cytoreductive surgery with the aim of reducing tumor burden to microscopic disease followed by adjuvant combined treatment with a platinum and taxane containing chemotherapy, which affords 80% of patients an initial complete response. However, Abdominal and pelvic recurrence rates are high and response to further chemotherapy is limited. Attempts at introducing biologic therapeutic agents to improve outcome in this disease are ongoing, while prognostic or predictive biomarkers that can stratify patients for treatment are still lacking. Using a 60-mer 22K oligonucleotide-based array comparative genome hybridization (CGH) platform combined with DNA isolated from microdissected tumor tissue samples, Birrer et. al. reported that the amplification of 5q31-35.3 in ovarian cancer cells is a negative prognostic indicator for patients with advanced stage high-grade serous ovarian cancer (HGSC). Further studies showed that fibroblast growth factor 1 (FGF1) located in the amplicon, may be one of the driving genes for ovarian cancer progression (Birrer et. al., 2007). Besides FGF1, located on the same amplicon is one of its receptors fibroblast growth factor receptor 4 (FGFR4), suggesting that it may also be amplified and may be another driving gene involved in ovarian cancer pathogenesis.In this study, we used microarrays to explore and compare gene expression profiles between FGFR4 knock down ovarian cancer cell lines and their corresponding parental cell lines. Two high grade serous ovarian cancer cell lines: SKOV3 and OVCA432 were selected for this study. For each of the cell lines, two different siRNA sequences which both target human FGFR4 were used. While a non-target scramble siRNA sequence was used as control. Ovarian cancer cells were transfected with siRNA using lipofectamine (Invitrogen). RNA extraction was performed 72 hours post-transfection, followed by hybridization on Affymetrix microarrays.
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Project description:Rhabdomyosarcoma (RMS) is a paediatric cancer driven either by a fusion protein (e.g. PAX3-FOXO1) or by mutations in key signalling molecules (e.g. RAS or FGFR4). Despite the latter giving potential for precision medicine approaches in RMS, there are no such treatments implemented in the clinic yet. In order to identify and test novel precision therapy strategies, appropriate cellular and mouse models are crucial. We have here thoroughly characterized a RMS patient-derived cell line model, RMS559, which harbours a FGFR4 V550L activating mutation with high allelic frequency (0.8). Importantly, we show that RMS559 cells are oncogenically dependent on FGFR4 signalling by treatment with the pan-FGFR inhibitor LY2874455. Phosphoproteomic analysis identified RAS/MAPK and PI3K/AKT as the major druggable signalling pathways downstream of FGFR V550L. Inhibitors against these pathways inhibited cell proliferation. Furthermore, we found that FGFR4 V550L is dependent on HSP90 and inhibitors targeting HSP90 efficiently restrain proliferation. Recently, FGFR4 specific inhibitors have been developed. While two of these, BLU-9931 and H3B-6527, did not efficiently inhibit FGFR4 V550L, probably because of the gatekeeper mutation (V550L), one of them, FGF401 inhibited FGFR4 V550L and cell proliferation at low nanomolar concentrations. Finally, we developed a mouse model using RMS559 cells and tested the in vivo efficacy of LY2874455 and FGF401. While LY2874455 inefficiently inhibited growth, FGF401 completely abrogated tumour growth in vivo.
2022-10-19 | PXD029719 | Pride
Project description:Fibroblast growth factor receptor 4 (FGFR4) aberrant expression and activity have been linked to the pathogenesis of a variety of cancers including rhabdomyosarcomas (RMS). We found that treatment of alveolar rhabdomyosarcoma (aRMS) cells with Guadecitabine (SGI-110), a next-generation DNA methyltransferase inhibitor (DNMTi), resulted in a significant reduction of FGFR4 protein levels, 5 days post treatment. Chromatin immunoprecipitation-sequencing (ChIP-seq) in aRMS cells revealed attenuation of the H3K4 mono-methylation across the FGFR4 super enhancer without changes in tri-methylation of either H3K4 or H3K27. These changes were associated with a significant reduction in FGFR4 transcript levels in treated cells. These decreases in H3K4me1 in the FGFR4 super enhancer were also associated with a 240-fold increase in KDM5B (JARID1B) mRNA levels. Immunoblot and immunofluorescent studies also revealed a significant increase in the KDM5B protein levels after treatment in these cells. KDM5B is the only member of KDM5 (JARID1) family of histone lysine demethylases that catalyzes demethylation of H3K4me1. These data together suggest a pleiotropic effect of DNMTi therapy in aRMS cells, converging to significantly lower FGFR4 protein levels in these cells.
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Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that fibroblast growth factor receptor 4 (FGFR4) drives this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-30 | GSE145326 | GEO
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We identified a subset of Luminal A primary breast tumors to give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that fibroblast growth factor receptor 4 (FGFR4) likely participates in this subtype switching. To evaluate this, we developed two FGFR4 genomic signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Bulk tumor gene expression analysis, and single cell RNAseq demonstrated that the inhibition of FGFR4 signaling caused molecular switching. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.
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Project description:The cJun NH2-terminal kinase (JNK)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.
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Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We observed that a subset of Luminal A primary breast tumors give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 drives this subtype switching. To evaluate this, we developed two FGFR4 signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-29 | GSE126037 | GEO
Project description:Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for breast cancer therapy. We observed that a subset of Luminal A primary breast tumors give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 drives this subtype switching. To evaluate this, we developed two FGFR4 signatures using a PDX model treated with a FGFR4 inhibitor (BLU9931), which inhibited PDX growth in vivo. Examining patient outcomes in the METABRIC breast cancer cohort showed that the FGFR4-induced and FGFR4-repressed signatures each predicted overall survival (OS) (HR=6.30, P<0.0001; HR=0.33; P<0.0001, respectively). Multivariate analysis showed that the FGFR4-induced signature was also an independent prognostic factor beyond subtype and stage for OS (HR=2.34, P=0.014). Supervised analysis of 77 primary tumors with paired metastasis revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting a treatment options for FGFR4-positive patients, whose high expression is non-genetically determined.
2020-07-29 | GSE126036 | GEO