Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA600850 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:In colorectal cancer, the role of the most common driver mutations in APC, KRAS, SMAD4 and TP53, on global mRNA translation are incompletely understood. To adress this, we generated and characterised mouse intestinal organoid models with oncogenic mutations in each of these genes using Cre-Lox recombination in ex vivo organoid cultures combined with stable expression of short hairpin RNAs. Microarray analysis was used to characterise transcriptomic reprogramming that supports altered global translation rates in mutant cells.
2020-05-31 | GSE143509 | GEO
Project description:Deregulated global mRNA translation is an emerging feature of cancer cells. Oncogenic transformation in colorectal cancer (CRC) is driven by mutations in APC, KRAS, SMAD4, and TP53, known as the adenoma-carcinoma sequence (ACS). Here we introduce each of these driver mutations into intestinal organoids to show that they are modulators of global translational capacity in intestinal epithelial cells. Increased global translation resulting from loss of Apc expression was potentiated by the presence of oncogenic Kras G12D Knockdown of Smad4 further enhanced global translation efficiency and was associated with a lower 4E-BP1-to-eIF4E ratio. Quadruple mutant cells with additional P53 loss displayed the highest global translational capacity, paralleled by high proliferation and growth rates, indicating that the proteome is heavily geared toward cell division. Transcriptional reprogramming facilitating global translation included elevated ribogenesis and activation of mTORC1 signaling. Accordingly, interfering with the mTORC1/4E-BP/eIF4E axis inhibited the growth potential endowed by accumulation of multiple drivers. In conclusion, the ACS is characterized by a strongly altered global translational landscape in epithelial cells, exposing a therapeutic potential for direct targeting of the translational apparatus.
| S-EPMC7568276 | biostudies-literature
Project description:Translational Reprogramming as a Driver of Antimony-drug Resistance in Leishmania
| PRJNA727294 | ENA
Project description:Purpose: In this study, we have used a translatomic approach by coupling polysome profiling and deep RNA-sequencing to estimate changes in the translatome of antimony-resistant Leishmania parasites Methods: Leishmania tropica promastigotes were stepwise selected for resistance to trivalent antimony. Two different strains were studied, the L. tropica SbIII-sensitive or wildtype strain (WT) and the derived highly resistant strain (HR). After polysome profiling four types of samples were evaluated by deep RNAseq: total mRNA used as input, monosomes (MS), light polysomes (LP), and heavy polysomes (HP). The DESeq2 algorithm was used for differential expression analysis to identify translational changes at the basal level (HR Vs. WT), translational changes to combat the drug (HR+SbIII Vs. HR), and to compare translatomic Vs. transcriptomic changes (HP Vs. Total input) [see overall design section below]. Results: Differential translational analysis (cutoff of fold change ≥ 1.5 and p-value corrected by Benjamini-Hochberg FDR ≤ 0.05) showed that transcripts composition per polysome fraction was different in the resistant strain. It included several upregulated (Up) and downregulated (Down) transcripts. At the basal level, 2431 different transcripts were differentially translated: monosome (Down: 4, Up: 0), light polysomes (Down: 906, Up: 951), and heavy polysomes (Down: 1096, Up: 1064). Under the antimony challenge, 189 different transcripts were differentially translated: monosome (Down: 0, Up: 2), light polysomes (Down: 9, Up: 57), and heavy polysomes (Down: 30, Up: 134). Overall, most of the changes were identified in polysome fraction when compared with monosomes or total transcriptome. Conclusions: Our study shows evidence that translational control has a main role in coordinating the resistance to antimony in Leishmania parasites. We propose a novel model that establishes translational control as a major driver of antimony-resistant phenotypes in Leishmania parasites.
2023-04-04 | GSE173848 | GEO
Project description:A patient-derived epithelium-only colon rectal organoid, also referred to as a colonoid, was generated from an adenoma (associated with a resection surgery of an invasive moderately differentiated colorectal adenocarcinoma) as part of the development of an on-going organoid biobank at the Michigan Medicine Translational Tissue Modeling Laboratory (TTML, www.UmichTTML.org). The genomic variant signature of this adenoma colonoid was characterized using whole exome sequencing in order to access genomic concordance between the source patient tissue (adenoma and histologically normal tissue 10 cm from lesion) and the in vitro culture, as well as to access genomic stability of the culture over time at 2 and 6.5 months in culture.
2020-12-22 | E-MTAB-9936 | biostudies-arrayexpress
Project description:AIM: To analyze the expression profiles of premalignant and/or preclinical lesions of gastric cancers. METHODS: We analyzed the expression profiles of normal gastric pit, tubular adenoma and carcinoma in situ using microdissected cells from routine gastric biopsies. For the DNA microarray analysis of formalin-fixed samples, we developed a simple and reproducible RNA extraction and linear amplification procedure applying two polymerase-binding sites. The amplification procedure took only 8 h and yielded comparable DNA microarray data between formalin-fixed tissues and unfixed controls. RESULTS: In comparison with normal pit, adenoma/carcinoma showed 504 up-regulated and 29 down-regulated genes at the expected false significance rate 0.15%. The differential expression between adenoma and carcinoma in situ was subtle: 50 and 22 genes were up-, and down-regulated in carcinomas at the expected false significance rate of 0.61%, respectively. Differentially expressed genes were grouped according to patterns of the sequential changes for the 'tendency analysis' in the gastric mucosa-adenoma-carcinoma sequence. CONCLUSION: Groups of genes are shown to reflect the sequential expression changes in the early carcinogenic steps of stomach cancer. It is suggested that molecular carcinogenic pathways could be analyzed using routinely processed biopsies. Keywords: other
2004-04-06 | GSE1279 | GEO
Project description:Transcriptional profiling of human adrenocortical tumors. Gene expression profile of normal adrenal cortex, hormonally inactive adenoma, cortisol-secreting Cushing-adenoma and primary adrenocortical cancer tissues were compared. The goal of this study was to identify significant differences in the gene expression of these groups. Further aim was to reveal biologically relevant pathogenetic pathways altered at transcriptional and posttranscriptional level, as well.
2009-07-01 | GSE14922 | GEO
Project description:mRNA profiles in PAF KO intestinal adenoma
2018-02-15 | GSE109209 | GEO
Project description:To assess the possible mechanisms by which UTP18 promotes adenoma carcinogenesis, RNA-seq assay was performed to compare UTP18 overexpress A0529 adenoma with scramble.
2020-05-01 | GSE142023 | GEO
Project description:We identified transcriptional landscape in pleomorphic adenoma (PA).
2024-07-14 | GSE180105 | GEO