Expression data of BRAF inhibitor resistant melanoma cells and spheroids
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ABSTRACT:
PROVIDER: PRJNA625260 | ENA |
REPOSITORIES: ENA
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Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
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Project description:The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ overcomes PLX4032 resistance, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and cytoskeletal tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a promising synthetic lethal strategy to suppress resistance in BRAF inhibitor therapies.
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Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
2020-11-18 | PXD020241 | Pride
Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
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