Oncogenic KRAS(G12V) and BRAF(V600E) in intestinal organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA474218 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7249340_1.fastq.gz | Fastqsanger.gz | |||
| SRR7249340_2.fastq.gz | Fastqsanger.gz | |||
| SRR7249341_1.fastq.gz | Fastqsanger.gz | |||
| SRR7249341_2.fastq.gz | Fastqsanger.gz | |||
| SRR7249342_1.fastq.gz | Fastqsanger.gz |
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Project description:Goals of the study was to compare transcripional and phenotypic response of mouse intestinal organoid cultures to the KRAS(G12V) or BRAF(V600E)oncogenes.
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Project description:The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF- B anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. This SuperSeries is composed of the following subset Series:; GSE17643: Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression; GSE17671: Profiling of immortalized human lung epithelial cells following infection with oncogenic KRAS (G12V) Experiment Overall Design: Refer to individual Series
2009-10-31 | E-GEOD-17672 | biostudies-arrayexpress
Project description:The goal of this study was to determine genes affected by expressing KRAS mutation (G12V) in NCI-H1703 cells This data was used in Meng Wang et. al. Cancer Research 2016 to determine the alterations of gene expression profiling associated with expression of KRAS mutation (G12V). The experiment uses a pBABE-Puro vector encoding KRAS G12V and a corresponding empty vector control.
2016-03-23 | E-GEOD-79486 | biostudies-arrayexpress
Project description:Transcriptiional profling of 13 normal lung samples, 18 lung KRAS(G12V) tumor samples, and 18 lung HER2(V659E) tumor samples 13 normal lung samples, 18 lung KRAS(G12V) tumor samples, and 18 lung HER2(V659E) tumor samples hybridized against Stratagene universal mouse reference RNA with dye swap
2009-11-30 | E-GEOD-18784 | biostudies-arrayexpress
Project description:BRAF(V600E) is a frequent mutation in colon cancer. We have analysed transcriptional effects of BRAF(V600E) in the intestinal epithelium of transgenic mice that harbour an inducible BRAF(V600E) transgene. Mice used in this experiment were compound transgenic for a stem-cell specific Lgr5-EGFP Reporter and either an inducible TdTomato-2A-BRAF(V600E) transgene or an inducibe TdTomato-luciferase transgene. Transgenes were induced by doxycycline (4mg/ml) treatment provided in a 1% sucrose solution in the drinking water of transgenic mice for 24h. Intestinal crypts were isolated by filtering (70um) following a PBS/EDTA incubation step. Single cell suspensions were made by digestion of crypts in 500ug/ml trypsine and 0.8u/ml DNAseI for approx. 20min at RT. Cell populations for profiling were isolated by FACS, using an Aria SOPR (BD), equipped with a 70um nozzle.
2013-12-31 | E-GEOD-50678 | biostudies-arrayexpress
Project description:Background Main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF- mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to define in this context the specific role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit and regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing the TCGA MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF V600E MM cell lines on their response to BRAF/MEKi in vitro. We performed a proteomic screening to identify proteins modulated by changes in RICTOR expression and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results We found that low RICTOR levels in MM correlate with an overall worse clinical outcome. GSEA of low- RICTOR tumors revealed a gene expression signature suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy producing pathway. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAFi/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. In RICTOR- depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, while their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils a novel tumor suppressing role for mTORC2 in the responses of BRAF V600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low- RICTOR tumors. Importantly, our findings support the concept that the evaluation of intra-tumor RICTOR levels in MM has a prognostic value, and may help predicting the response of patients to targeted therapy.
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Project description:In the human EGFR mutant adenocarcinoma cell line PC9 pBabe empty vector (EV) or BRAF V600E were overexpressed. RNA was extracted from EV, BRAF V600E overexpressing or osimertinib-resistant BRAF V600E expressing cells after 48h treatment with osimertinib, trametinib, a combination of both or vehicle controls. RNA was subjected to 3' UTR RNA sequencing.
2021-10-20 | E-MTAB-11004 | biostudies-arrayexpress
Project description:Multiplexed PRM analysis for metabolic reprogramming in isogenic cell lines with KRAS or BRAF mutations.
2016-02-01 | MSV000079486 | GNPS
Project description:The goal of this study was to determine genes affected by expressing KRAS mutation (G12V) in NCI-H1703 cells This data was used in Meng Wang et. al. Cancer Research 2016 to determine the alterations of gene expression profiling associated with expression of KRAS mutation (G12V).
2016-03-23 | GSE79486 | GEO
Project description:The accumulation of mutations in cancer driver genes such as tumor suppressors or pro-to-oncogenes affects cellular homeostasis. Disturbances in the mechanism controlling prolifera-tion causes significant augmentation of cell growth and division due to the loss of sensitivity to the regulatory signals. Nowadays, an increasing number of cases of liver cancer are observed worldwide. Data provided by the International Cancer Genome Consortium (ICGC) have indi-cated many alterations within gene sequences, whose roles in tumor development are not well understood. A comprehensive analysis of liver cancer (hepatocellular carcinoma-virus associated) samples has identified new and rare mutations in B-Raf proto-oncogene (BRAF) in Japanese HCC patients, as well as BRAF V600E mutations in French HCC patients. However, their function on liver cancer has never been investigated. Here, using tests for functional analysis and next gen-eration sequencing we demonstrate the tumorigenic effect of BRAF V600E on hepatocytes (THLE-2 cell line). Moreover, we identified genes such as BMP6, CXCL11, IL1B, TBX21, RSAD2, MMP10, SERPIND1, which are possibly regulated by BRAF V600E-mediated mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway. Through several functional assays, we demonstrated that BRAF L537M, D594A, and E648G mutations by its own are not pathogenic in liver cancer. The investigation of genome mutations and the de-termination of their impact on cellular processes and functions are crucial to unraveling the mo-lecular mechanisms of liver cancer development.
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