Analysis of CRISPR‐Cas9 screens identifies genetic dependencies in melanoma

Christodoulou, Eirini; Rashid, Mamunur; Pacini, Clare; Droop, Alastair; Robertson, Holly; Groningen, Tim van; Teunisse, Amina F.A.S.; Iorio, Francesco; Jochemsen, Aart G.; Adams, David J.; Doorn, Remco van

doi:10.1111/pcmr.12919

Cited by 14 publications

(12 citation statements)

References 45 publications

(73 reference statements)

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“…Detailed understanding of the role of genes and proteins in key signaling pathways in melanoma development has led to the designation of new targets for the treatment of melanoma. Recently, analysis of CRISPR-CAS9 screens has identified genes that have not previously been associated with melanoma growth and that can be targeted using available inhibitors, thus opening new treatment strategies that may be explored in the near future as potential therapeutic targets [ 167 ]. Furthermore, in the future, more clinical trials and more data on OS and response rates need to be collected to find the best combination treatment and the best possible sequence of combination therapy to manage the complexity of melanoma treatment.…”

Section: Discussionmentioning

confidence: 99%

Molecular Markers and Targets in Melanoma

Teixidó

Castillo

Martinez-Vila

et al. 2021

Cells

101

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Melanoma develops as a result of several genetic alterations, with UV radiation often acting as a mutagenic risk factor. Deep knowledge of the molecular signaling pathways of different types of melanoma allows better characterization and provides tools for the development of therapies based on the intervention of signals promoted by these cascades. The latest World Health Organization classification acknowledged the specific genetic drivers leading to melanoma and classifies melanocytic lesions into nine distinct categories according to the associate cumulative sun damage (CSD), which correlates with the molecular alterations of tumors. The largest groups are melanomas associated with low-CSD or superficial spreading melanomas, characterized by frequent presentation of the BRAFV600 mutation. High-CSD melanomas include lentigo maligna type and desmoplastic melanomas, which often have a high mutation burden and can harbor NRAS, BRAFnon-V600E, or NF1 mutations. Non-CSD-associated melanomas encompass acral and mucosal melanomas that usually do not show BRAF, NRAS, or NF1 mutations (triple wild-type), but in a subset may have KIT or SF3B1 mutations. To improve survival, these driver alterations can be treated with targeted therapy achieving significant antitumor activity. In recent years, relevant improvement in the prognosis and survival of patients with melanoma has been achieved, since the introduction of BRAF/MEK tyrosine kinase inhibitors and immune checkpoint inhibitors. In this review, we describe the current knowledge of molecular pathways and discuss current and potential therapeutic targets in melanoma, focusing on their clinical relevance of development.

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Section: Discussionmentioning

confidence: 99%

Molecular Markers and Targets in Melanoma

Teixidó

Castillo

Martinez-Vila

et al. 2021

Cells

101

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“…The analysis was identical to that described in Christodoulou et al . [ 37 ], except that we used data on all 29 melanoma cell lines released by the Broad Institute [ 34 ].…”

Section: Methodsmentioning

confidence: 99%

“…Finally, the P values were adjusted for multiple testing using the FDR method. The analysis was identical to that described in Christodoulou et al [37], except that we used data on all 29 melanoma cell lines released by the Broad Institute [34].…”

Section: Gene Dependency Analysismentioning

confidence: 99%

“…(C) CRISPR lethality scores (higher scores correspond to a larger reduction in cell viability when the specific gene is silenced) of eight genes associated with lethality/reduced cellular fitness in skin cancer cell lines (Fisher's exact test, p-adj < 0.01) versus all other cell lines in the Broad DepMap collection [34]. These data and the analysis approach used were described in detail in Christodoulou et al [37]. Red indicates a negative effect of CRISPR on cancer cell line fitness.…”

Section: Essentiality Of Primary Melanoma Driversmentioning

confidence: 99%

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Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma

Birkeälv

Harland

Matsuyama

et al. 2022

The Journal of Pathology

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Melanoma is a heterogenous malignancy with an unpredictable clinical course. Most patients who present in the clinic are diagnosed with primary melanoma, yet large-scale sequencing efforts have focused primarily on metastatic disease. In this study we sequence-profiled 524 American Joint Committee on Cancer Stage I-III primary tumours. Our analysis of these data reveals recurrent driver mutations, mutually exclusive genetic interactions, where two genes were never or rarely co-mutated, and an absence of co-occurring genetic events. Further, we intersected copy number calls from our primary melanoma data with whole-genome CRISPR screening data to identify the transcription factor interferon regulatory factor 4 (IRF4) as a melanoma-associated dependency.

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“…shown that the genetic inactivation of DUSP4 reduced the proliferation of melanoma cells, thus making DUSP4 an interesting therapeutic target (Christodoulou et al, 2021). DUSP4 is expressed in different tissues, including the eye, and more importantly in retinal BCs (Supplementary Table S6,.…”

Section: Bdnf (Mim# 113505) Encoding Brain-derived Neurotrophic Facto...mentioning

confidence: 99%

Shedding light on myopia by studying complete congenital stationary night blindness

Zeitz¹,

Roger²,

Michiels³

et al. 2022

Acta Ophthalmologica

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Purpose: Myopia is the most common eye disorder, caused by heterogeneous genetic and environmental factors. Rare inherited retinal disorders are often associated with high myopia. Genes implicated in myopia encode proteins involved in eye morphogenesis, extracellular matrix organization, visual perception, circadian rhythms, and retinal signalling. Differentially expressed genes (DEGs) identified in animal models mimicking myopia are helpful in suggesting candidate genes implicated in human myopia. Complete congenital stationary night blindness (cCSNB) in humans and animal models represents an ON‐bipolar cell signal transmission defect and is also associated with high myopia. The purpose of this work was to identify the molecular cause of myopia present in cCSNB. Methods: A whole transcriptome sequencing (RNA‐seq) approach was performed using retina from three mouse lines with cCSNB, Gpr179−/−, Lrit3−/− and Grm6−/− and the expression data compared to data of age‐matched wild‐type littermates (n = 5). DEGs with fold changes of at least 1.2, p‐values of ≤0.01, an expression value of at least 5 transcripts per million reads and appearing in at least two cCSNB mouse lines were investigated in detail. A meta‐analysis was performed by (a) comparing our data with published transcriptome data from purified retinal cells and single cell RNA‐Seq data, (b) pathway analyses, (c) myopia databases and publications concerning their role in normal vision. Several of the DEGs were validated by RT‐qPCR experiments and analysed by western blot and immunolocalization studies. Results: More than 50 DEGs were found in at least two cCSNB mouse lines. Expression of those was found in different retinal cell types. The difference in expression was independent of the number of nuclei present in wild‐type and mutant inner retina. Pathway analysis revealed that mitogen‐activated protein kinase pathways, synaptic signalling, G protein‐coupled receptor ligand binding pathways, and proteins implicated in eye, endoderm and connective tissue development were affected in cCSNB. More than half of the genes were already associated with myopia. Conclusions: Our study reveals DEGs in all retinal cell types of cCSNB models, previously associated with myopia and novel candidates. These studies combined with pathway analyses provide the basis for the development of pharmacological and optical myopia therapies.

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Analysis of CRISPR‐Cas9 screens identifies genetic dependencies in melanoma

Cited by 14 publications

References 45 publications

Molecular Markers and Targets in Melanoma

Molecular Markers and Targets in Melanoma

Mutually exclusive genetic interactions and gene essentiality shape the genomic landscape of primary melanoma

Shedding light on myopia by studying complete congenital stationary night blindness

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