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Generating a RAS expression signature in neuroblastoma

ABSTRACT: Mutations affecting the RAS-MAPK pathway frequently occur in relapse neuroblastoma tumors, which suggests that activation of this pathway is associated with a more aggressive phenotype. To explore this hypothesis we generated several model systems to define a neuroblastoma RAS-MAPK pathway signature. We could show that activation of this pathway in primary tumors indeed correlates with poor survival and is associated with known activating mutations in ALK and other RAS-MAPK pathway genes. From integrative analysis we could show that mutations in PHOX2B, CIC and DMD are also associated with an activated RAS-MAPK pathway. Mutation of PHOX2B and deletion of CIC in neuroblastoma cell lines induces activation of the RAS-MAPK pathway. This activation was independent of phosphorylated ERK in the CIC knock out systems. Furthermore, deletion of CIC causes a significant increase in tumor growth in vivo. These results show that the RAS-MAPK pathway is involved in tumor progression, and establish CIC as a powerful tumor suppressor that functions downstream of this pathway in neuroblastoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115406 | GEO | 2018/08/22

REPOSITORIES: GEO

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PHOX2B promotes the occurrence and development of neuroblastoma by activating the MAPK signaling pathway

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Project description:We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance.

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| EGAS00001001183 | EGA

ena-DATASET-AMC-11-05-2015-14:58:16:693-185 - samples

| EGAD00001001360 | EGA

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2019-03-06 | PXD011551 | Pride

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2018-05-31 | E-MTAB-6681 | biostudies-arrayexpress

ChIP-seq of CIC (Capicua) and histone marks (H3K9ac, H3K27ac and H3K4me1) in glioma neural stem cells (GNS) G144, human foetal neural stem cells (hNSC) and mouse embryonic stem cells (mESC),

Project description:We identified genome-wide binding patterns of CIC in several different cell types and find that CIC target genes are enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to its target genes is abolished by high MAPK activity, which leads to hyperacetylation and their transcriptional activation. Inhibition of MAPK signaling via MEK inhibition leads to recruitment of CIC to its target genes. Expression data of G144 cells after MEK inhibition and CIC knockout is available under accession E-MTAB-6681

2018-05-31 | E-MTAB-6682 | biostudies-arrayexpress

Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cellsLinking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells

Project description:Background: The Ras pathway genes KRAS, BRAF or ERBBs have somatic mutations in ~60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway, or whether they have acquired mutations in genes hitherto not known to belong to the pathway. Methods: To address the second possibility, and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Results: Of the 163 recurrently targeted genes in the two different genetic backgrounds, one third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, 9 genes also mutated in human colorectal cancers were identified. Among these, stable knock-down of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knock-down of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. Conclusions: This work establishes a proof-of-concept that human cell based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.

2018-02-20 | PXD008382 | Pride

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