Activation of RAS/MEK/ERK signaling drives biliary differentiation in primary liver cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA989110 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25072917_1.fastq.gz | Fastqsanger.gz | |||
| SRR25072917_2.fastq.gz | Fastqsanger.gz | |||
| SRR25072918_1.fastq.gz | Fastqsanger.gz | |||
| SRR25072918_2.fastq.gz | Fastqsanger.gz | |||
| SRR25072919_1.fastq.gz | Fastqsanger.gz |
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Project description:Activation of RAS/MEK/ERK signaling drives biliary differentiation in primary liver cancer [396UE]
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Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.
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Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
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Project description:About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results.
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Project description:NRAS activating mutations occur in 15-25% of melanoma patients. However, this subtype is more aggressive and refractory to current treatment modalities, including targeted MEK inhibitors, immunotherapies, and the recently emerging RAS inhibitors. Accordingly, identifying novel therapeutic targets and designing novel antimelanoma strategies is of utmost clinical relevance. Melanomas often harbor hyperactive nitric oxide synthases (NOS) which correlates strongly with poor prognosis. NOS is also known to be activated by ERK signaling. The nitric oxide so produced, induces nitrosylation, a post-translational modification, which dysregulates various kinases and phosphatases. We sensitized NRAS-mutant melanomas to targeted MEK inhibitors by inhibiting nitrosylation. This outcome revealed a strong correlation between global de-nitrosylation and downregulation of MEK-ERK cascade with a concomitant de-nitrosylation of NRAS and other small GTPases like Rho and Rac, dual specificity phosphatases, and ribosomal S6 kinase. In vivo, we observed extreme regression of NRAS-mutant melanoma tumors generated in an immunocompetent mouse model in response to a sequential nitrosylation inhibition and MEK inhibition. In addition to MEK-ERK downregulation, this strategy activated the CD8+ T cells in the tumor microenvironment. We conclude that while nitrosylation hyperactivates the RAS-RAF-MEK-ERK cascade, it also suppresses anti-melanoma immune response, bolstering progression and MEKi resistance. The underlying mechanism(s) will be crucial in identifying novel therapeutic vulnerabilities against aggressive, currently incurable NRAS-mutant melanomas with potential clinical application in other melanoma subtypes.
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Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials. 83 microarrays: Mouse control (15), Mouse neurofibroma (15), Mouse MPNST (18); Human nerve (3), Human neurofibroma (26), Human MPNST (6) We used the same human tumor samples as in series GSE14038 (dNF, pNF and MPNST). However, instead of referencing gene expression changes to the normal human Schwann cell samples (NHSC) as we did in series GSE14038, we generated three (new) normal nerve samples (samples jan-N1-3) and referenced gene expression changes to those samples. Moreover, the analysis of series GSE14038 evaluated changes in expression between NHSC, benign tumor subtypes (dNF and pNF), and malignant tumors (MPNST), while our present submission evaluated changes between normal nerve, benign tumors (combined dNF and pNF),and malignant tumors (MPNST). The Series supplementary 'merged_data.txt' file contains the data for 9,891 transcripts that were statistically different in at least one of the two species and present in both mouse and human data sets.
2012-12-28 | E-GEOD-41747 | biostudies-arrayexpress