CH6824025, potent and selective DDR1 inhibitor, reduces kidney fibrosis in UUO mice
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ABSTRACT:
PROVIDER: PRJNA1144400 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30133653.fastq.gz | Fastqsanger.gz | |||
| SRR30133654.fastq.gz | Fastqsanger.gz | |||
| SRR30133655.fastq.gz | Fastqsanger.gz | |||
| SRR30133656.fastq.gz | Fastqsanger.gz | |||
| SRR30133657.fastq.gz | Fastqsanger.gz |
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Project description:Discoidin domain receptor 1 (DDR1) is a collagen receptor with tyrosine kinase activity, and its expression is enhanced in various disease conditions. Although previous research suggests that DDR1 contributes to renal disease progression, DDR1 inhibitors for renal fibrosis have yet to be developed. In this study, we used unilateral ureteral obstruction (UUO) mice to investigate whether CH6824025, a strong and selective DDR1 phosphorylation inhibitor, can improve renal fibrosis. Furthermore, to analyze its action in detail, we performed 10x Visium spatial transcriptomics (ST) analysis on the kidney. Orally administered CH6824025 suppressed the phosphorylation of DDR1 in renal tissue, and the amount of hydroxyproline, the Sirius red-positive area, and the mRNA expression of fibrosis and inflammation-related genes in the kidney were significantly decreased. 10x Visium ST analysis suggested that DDR1 is mainly expressed in distal nephrons under normal conditions, but that its expression appears to increase in the injured proximal tubules in UUO mice. Comparing mRNA expression in DDR1 positive spots in the vehicle and the CH6824025 administration group, oxidative phosphorylation and mitochondrial dysfunction were improved, and pathways involved in fibrosis inhibited in the CH6824025 administration group. Downstream analysis suggested that mRNA expression changes in the CH6824025 administration group contribute to the inhibition of cell movement. Taken together, our findings suggest that CH6824025 inhibited the migration of inflammatory cells to the injury site in UUO mice, reduced inflammation, and brought about the maintenance of cell homeostasis and inhibition of fibrosis. DDR1 inhibitors are expected to be a promising treatment for renal fibrosis.
2024-12-31 | GSE273978 | GEO
Project description:Examination of effect of stable DDR1 knockdown by shRNA on transcriptional profile in BXPC3 cell line to understand role of DDR1 in tumorigenesis. Transcriptional profiles of parental BXPC3 cell line was compared to BXPC3 cells stably transfected with non-target shRNA or DDR1 shRNA, N=3 for each condition.
2014-05-01 | E-GEOD-39207 | biostudies-arrayexpress
Project description:Examination of effect of stable DDR1 knockdown by shRNA on transcriptional profile in BXPC3 cell line to understand role of DDR1 in tumorigenesis.
2014-05-01 | GSE39207 | GEO
Project description:Development of potent and selective KDM5 covalent inhibitors
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Project description:Purpose: The goals of this study are to compare mammary tumor transcriptome profiling with or without DDR1 in immunocompetent mice in an unbiased way. Methods: In vitro samples: DDR1 WT or KO in vitro cultured E0771 cells were sequenced. Rag1-/- samples: DDR1 WT or KO E0771 cells were injected in Rag1-/- mice, and tumors were harvested and sequenced. C57BL/6 samples: DDR1 WT or KO E0771 cells were firstly inoculated into Rag1-/- mice. When tumor volume reached approximately 200~300 mm3 (usually 20 days after inoculation), 60 mg of tumor organoid were transplanted to WT C57BL/6 mice. Tumor samples were collected on day 4 after transplantation for RNA-seq. Antibody treatment samples: DDR1 KO E0771 cells were reconstituted with human DDR1, then injected into C57BL/6 mice. Isotype control IgG or anti-hDDR1 ECD antibody treatment (10mg/kg intrutumural) started when tumor volume reached approximately 100 mm3. Tumor samples were collected on day 6 after treatment for RNA-seq. Results: Approximately 50 million sequence reads were obtained per sample and identified more than 20,000 transcript isoforms. Conclusions: The RNA-seq results represents the detailed analysis of DDR1 WT/KO mammary tumor transcriptomes in immunocompetent mice C57BL/6.
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Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.
2018-01-31 | PXD008546 | Pride
Project description:The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. For instance, patients harbouring oncogenic mutations in RAS signalling do not respond to anti-EGFR targeted treatment. Therefore, RAS-independent therapies are needed. Interestingly nilotinib, a clinically approved drug for chronic myeloid leukaemia, inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS-independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1-mediated BCR phosphorylation on Tyr177, which is important for maintaining -catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient-derived metastatic and circulating CRC cell lines.
2018-01-31 | PXD008582 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer, frequently progressing and spreading by liver metastasis. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support or restrain PDAC progression and may impede blood supply and nutrient availability. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-kB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are iCol I enriched and DDR1 and NRF2 low have improved median survival compared to those with high cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-kB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. The diverse effects of the tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-kB-NRF2-mitochondrial biogenesis pathway, presenting new therapeutic opportunities.
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Project description:Amorfrutins are selective PPARγ agonists with potent antidiabetic properties
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Project description:Receptor tyrosine kinase DDR1 (Discoidin Domain Receptor 1) interacts with the extracellular matrix (ECM) to promote tumor cell proliferation through its intracellular kinase activity, while its extracellular non-enzymatic domain creates a physical barrier for immune evasion. Although DDR1 inhibitors and antibodies have been developed, targeting DDR1 kinase activity alone cannot fully block the biological effects mediated by its scaffold function. Therefore, developing DDR1 degraders presents a potentially more effective therapeutic strategy. Through screening a proprietary small-molecule ubiquitination library, we identified NSC632839, which significantly induces DDR1 protein degradation. Mechanistically, chemical proteomics and genetic studies demonstrated that NSC632839 functions by inhibiting USP7, which interacts with, stabilizes, and deubiquitinates DDR1, preventing its proteasomal degradation. Importantly, we observed that TP53 loss or mutation in tumor cells and clinical samples markedly upregulates DDR1 expression, thereby enhancing its interaction with USP7. Treatment with NSC632839 restores TP53 expression, resulting in a significant reduction in DDR1 levels. In various preclinical models, targeting USP7 with NSC632839 effectively eliminates tumor cells, offering a promising therapeutic strategy to overcome tumor relapse driven by TP53 mutations, both in vitro and in vivo. This study highlights the potential of DDR1 degradation via USP7 inhibition as a novel approach to treat TP53 mutation-enriched tumors.
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