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COLO829 treatment with PLX4032 and/or MITF knockdown

ABSTRACT: Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50649 | GEO | 2014/01/14

SECONDARY ACCESSION(S): PRJNA218481

REPOSITORIES: GEO

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COLO829 treatment with PLX4032 and/or MITF knockdown

Project description:Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. COLO829 human melanoma cell line harboring the BRAFV600E mutation was treated with BRAF inhibtior PLX4032 (Vemurafenib) and/or a hairpin against MITF

2014-01-14 | E-GEOD-50649 | biostudies-arrayexpress

MITF ChIP-seq in primary melanocyte and melanoma as a function of oncogenic BRAF

Project description:Thousands of enhancers are characterized in the human genome, yet few have been shown important in cancer. Inhibiting oncokinases, such as EGFR, ALK, HER2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by upregulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific MET enhancers for multiple common tumor types, including a melanoma lineage-specific MET enhancer that displays inducible chromatin looping and MET gene induction upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro- and anti-oncogenic functions of tumor lineage-enriched transcription factors mediating innate resistance to oncokinase therapy. MITF ChIP-seq was performed in primary human melanocytes with overexpression of BRAFV600E or a lentiviral control (RFP), and in COLO829 melanoma cells treated with DMSO, or PLX4032

2014-01-14 | E-GEOD-50681 | biostudies-arrayexpress

MITF ChIP-seq in primary melanocyte and melanoma as a function of oncogenic BRAF

2014-01-14 | GSE50681 | GEO

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

Project description:Increased MITF expression contributes to melanoma progression and resistance to BRAF pathway inhibition. We show that, unexpectedly, lack of MITF is associated with more severe resistance to a range of inhibitors. Indeed, the presence of endogenous MITF was essential for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlated with expression of several activated receptor tyrosine kinases, most commonly AXL. The MITF-low/AXL-high/drug resistance phenotype was seen in roughly half of BRAF mutant and the majority of NRAS mutant melanoma cell lines. The dichotomous behavior of MITF in drug response was corroborated in vemurafenib-resistant biopsies, including MITF high and low clones in a relapsed patient. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. Experssion analysis by RNAseq of 14 melanoma cell lines.

2014-09-19 | E-GEOD-61544 | biostudies-arrayexpress

Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

2014-09-19 | GSE61544 | GEO

BRAF/MAPK and GSK3 signaling converges to control MITF nuclear export

Project description:The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulatedin cancer. In principle, combinatorial posttranslational modification of key lineage specific transcription factors would be an effective mean stointegrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcriptionfactoriscontrolledremainspoorlyunderstood.Here,we showthatGSK3,downstreamfromboththePI3KandWntpathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activatinga previously unrecognizedhydrophobic exportsignal. NonmelanocyteMITFisoformsexhibitpoorregulationbyMAPKsignaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import–export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.

2019-11-12 | PXD010782 | Pride

BRAF/MAPK and GSK3b signalling signaling converge to control MITF nuclear export

Project description:The close integration of the MAPK, PI3K and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial post-translational modification of key lineage–specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia associated transcription factor, MITF, plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts and mast cells, and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell cycle progression, cell migration, metabolism and lysosome biogenesis. Yet how the activity of this key transcription factor is controlled remains poorly understood. Here we show that GSK3b, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3b, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import-export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal

2022-02-28 | PXD010665 | Pride

Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF

Project description:We evaluated two matched human cell lines derived from primary melanocytes, termed pmel+BRAF(V600E) and pmel+BRAF(V600E)+MITF. These cells are therefore isogenic with the exception of the expression of MITF. Gene Set Enrichment Analysis of microarray data identified a highly significant induction of oxidative phosphorylation gene set in MITF expressing cells compared to control cells.

2013-03-07 | E-GEOD-38007 | biostudies-arrayexpress

miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling

Project description:The onset of secondary resistance represents a major limitation to long term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is key to the rational design of alternative therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-seq in MET-addicted gastric and lung cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, increased miR-205 expression determined the downregulation of the EGFR inhibitor ERRFI1, which, in turn, caused EGFR activation and MET-TKI resistance. MiR-205/ERRFI1 driven EGFR activation rendered MET-TKI resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this newly identified mechanism of adaptive resistance, we report that a patient with a MET amplified lung adenocarcinoma displayed deregulation of the miR-205/ERRFI1 axis in concomitance with the onset of clinical resistance to anti-MET therapy.

2018-07-16 | GSE114406 | GEO

MITF deficiency accelerates GNAQ-driven uveal melanoma

Project description:Cutaneous melanoma (CM) and uveal melanoma (UM) both originate from the melanocytic lineage but are primarily driven by distinct oncogenic drivers, BRAF/NRAS or GNAQ/GNA11 respectively. The melanocytic master transcriptional regulator, MITF, is essential for both CM development and maintenance, but its role in UM is largely unexplored. Here, we use zebrafish models to dissect the key UM oncogenic signaling events, and establish the role of MITF in UM tumors. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K. To further explore the role of MITF in GNAQ-driven tumorigenesis, we performed phospho-proteomics and total proteomics on 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K tumors and 5 zebrafish GNAQ Tg(mitfa:GNAQQ209L);tp53M214K/M214K;mitfa-/- tumors.

2023-03-11 | PXD030527 | Pride

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