MITF deficiency accelerates GNAQ-driven uveal melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA788496 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17219901.fastq.gz | Fastqsanger.gz | |||
| SRR17219903.fastq.gz | Fastqsanger.gz | |||
| SRR17219905.fastq.gz | Fastqsanger.gz | |||
| SRR17219907.fastq.gz | Fastqsanger.gz | |||
| SRR17219909.fastq.gz | Fastqsanger.gz |
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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
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. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP and PLCβ-ERK, was also investigated in this system, and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLC4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(GNAQQ209L);tp53M214K/M214K or Tg(CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53-wildtype UM development, and allowed Tg(PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa-/- UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa-/- fish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCβ signaling. Collectively, these data show that YAP signaling is the major mediator of UM, and that MITF acts as bona fide tumor suppressor in UM, in direct opposition to its essential role in CM.
2022-04-27 | GSE190802 | GEO
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. Using a melanocytic lineage expression system, we showed that patient-derived mutations of GNAQ (GNAQQ209L) or its upstream CYSLTR2 receptor (CYSLTR2L129Q) both drive UM when combined with a cooperating mutation, tp53M214K/M214K. The tumor-initiating potential of the major GNAQ/11 effector pathways, YAP, and phospholipase C-β (PLCβ)–ERK was also investigated in this system and thus showed that while activated YAP (YAPAA) induced UM with high potency, the patient-derived PLCβ4 mutation (PLCB4D630Y) very rarely yielded UM tumors in the tp53M214K/M214K context. Remarkably, mitfa deficiency was profoundly UM promoting, dramatically accelerating the onset and progression of tumors induced by Tg(mitfa:GNAQQ209L);tp53M214K/M214K or Tg(mitfa:CYSLTR2L129Q);tp53M214K/M214K. Moreover, mitfa loss was sufficient to cooperate with GNAQQ209L to drive tp53–wild type UM development and allowed Tg(mitfa:PLCB4D630Y);tp53M214K/M214K melanocyte lineage cells to readily form tumors. Notably, all of the mitfa−/− UM tumors, including those arising in Tg(mitfa:PLCB4D630Y);tp53M214K/M214K;mitfa−/− zebrafish, displayed nuclear YAP while lacking hyperactive ERK indicative of PLCβ signaling. Collectively, these data show that YAP signaling is the major mediator of UM and that MITF acts as a bona fide tumor suppressor in UM in direct opposition to its essential role in CM.
| S-EPMC9172632 | biostudies-literature
Project description:We used microarray to compare global gene expression profiles between 5 GNAQ/11 mutant uveal melanoma cell lines (GNAQ mutant: 92-1, omm1.3, mel270; GNA11 mutant: omm-gn11 and upmd-1) and 5 GNAQ/11 wild type melanoma cell lines(sk-mel-2, mm415, mm485, sk-mel-5 and mum2c). Uveal melanoma is the most common intraocular tumor that mainly metastasizes to the liver in about 50% patients. Over 80% of UMs harbor GNAQ or GNA11 activating mutation. Currently there is no effective treatment available for UM patients. Results provide insights into downstream signaling of oncogenic GNAQ/11 and identification of therapeutic targets in UM.
2017-07-01 | GSE93666 | GEO
Project description:Mutations in the Gα-genes GNAQ and GNA11 are found in 85-90% of uveal melanomas (UMs). We analyzed the association between GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. Our analysis showed a shorter disease-specific survival of GNA11-mutated cases as compared to those carrying a GNAQ mutation (HR=1.97 [95%CI 1.12-3.46], p=0.02). GNA11 mutated UMs displayed a shorter, but not significant, median months survival of 26.97 [95% CI 25.02-37.08] versus GNAQ patients median months survival of 31.5 [95% CI 30.97-53.51]. The GNA11 mutation was also associated with: i) an increased frequency of loss of BRCA1-associated protein 1 (BAP1) expression (p=0.0005), ii) monosomy of chromosome 3 (p<0.001), iii) amplification of chr8q (p=0.038), iv) the combination of the latter two (p=0.0002), and inversely with v) chr6p gain (p=0.003). We used tandem-affinity-purification and mass spectrometry to show that the two derived G-proteins have different protein interaction partners. Specifically, the Tet Methylcytosine Dioxygenase 2(TET2), a protein that is involved in DNA demethylation, physically interacts with the GNAQ protein but not with GNA11, as confirmed by immunoprecipitation analyses. High-risk UM cases show a clearly different DNA-methylation pattern, suggesting that a different regulation of DNA methylation by the two G-proteins might convey a different risk of progression.
2023-02-27 | GSE197656 | GEO
Project description:Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, with a highly aggressive form of metastasis that is refractory to current therapies. UM is driven by aberrant activation of the Gαq pathway by hotspot activating mutation of GNAQ/GNA11, with few additional genetic aberrations. Despite this, there are limited effective targeted therapies currently available against the treatment of UM and mUM. Here, we performed a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with that of BRAF-mutant skin cutaneous melanoma, as a network chemical biology-based approach to identify therapeutic agents that target the mechanistic underpinnings driving UM. We observed strong genotype-driven drug sensitivities, and identified several drug classes with preferential activity against UM using a method termed Drug Set Enrichment Analysis (DSEA). Among them, we found an enrichment for PKC inhibitors, and identified one compound LXS-196, with the highest preferential activity against UM. Our investigation into the mechanism of action of LXS-196 revealed that in addition to inhibiting the Gq-ERK pathway, unlike other PKC inhibitors, this drug also reduced FAK activity, a recently identified mediator of non-canonical Gαq-driven oncogenic signaling. Kinome profiling revealed that LXS-196 acts as a multi-targeted kinase inhibitor, with high preference for PKC as well as PKN/PRK, the latter a poorly investigated AGC kinase that is activated directly by RhoA. This primes LXS-196 to target cell-essential pathways that drive tumor growth in UM by targeting both PKC, in addition to FAK. Moreover, we find that PKN is activated by GNAQ downstream from RhoA, thereby contributing to FAK stimulation. These findings expose a signaling vulnerability that can be targeted pharmacologically. Ultimately, dual PKC and PKN inhibition by LXS-196 acts synergistically with FAK inhibitors (FAKi) to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus providing a highly translatable therapeutic multimodal precision strategy against mUM.
2024-01-23 | PXD038023 | Pride
Project description:MITF deficiency and oncogenic GNAQ each promote proliferation programs in zebrafish melanocyte lineage cells
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Project description:Uveal melanoma (UM) is the most common primary malignancy of the eye in adults, but lacks any FDA-approved therapy for the deadly metastatic disease. Thus, there is great need to dissect the driving mechanisms for UM, and develop strategies to evaluate potential therapeutics. Using a zebrafish model, we previously identified MITF, the master melanocyte transcription factor, as a tumor suppressor in GNAQQ209L-driven UM. Here, we show that zebrafish mitfa-deficient GNAQQ209L-driven tumors significantly up-regulate neural crest markers, and higher expression of a melanoma-associated neural crest signature correlates with poor UM patient survival. We further determined how the mitfa-null state, as well as expression of GNAQQ209L, YAPS127A;S381A, or BRAFV600E oncogenes, impacts melanocyte lineage cells before they acquire the transformed state. Specifically, examination 5 days post-fertilization showed that mitfa-deficiency is sufficient to upregulate pigment progenitor and neural crest markers, while GNAQQ209L expression promotes a proliferative phenotype that is further enhanced by YAPS127A;S381A co-expression. Finally, we show that this oncogene-induced proliferative phenotype can be used to screen chemical inhibitors for their efficacy against the UM pathway. Overall, this study establishes that a neural crest signature correlates with poor UM survival, and describes an in vivo assay for pre-clinical trials of potential UM therapeutics.
2022-07-25 | GSE197927 | GEO
Project description:We developed an isogenic melanocytic cellular system and systematically examined the hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (e.g. L129Q) in human uveal melanoma. Biochemical and cell viability assays validated YM-254890 as a potent inhibitor of cell signaling and growth. Human uveal melanoma cells and mouse models recapitulated this finding, indicating that YM is also effective in vivo. Combination of YM and MEK inhibition leads to further decreases in MAPK pathway gene expression and cell viability. Furthermore, our cellular and mouse models show that combination leads to long term signaling inhibition and significant decreases in tumor burden.
2020-12-31 | GSE160112 | GEO
Project description:We developed an isogenic melanocytic cellular system and systematically examined the hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (e.g. L129Q) in human uveal melanoma. Biochemical and cell viability assays validated YM-254890 as a potent inhibitor of cell signaling and growth. Human uveal melanoma cells and mouse models recapitulated this finding, indicating that YM is also effective in vivo. Combination of YM and MEK inhibition leads to further decreases in MAPK pathway gene expression and cell viability. Furthermore, our cellular and mouse models show that combination leads to long term signaling inhibition and significant decreases in tumor burden.
2020-12-31 | GSE152705 | GEO