Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Metabolic reprogramming driven by TFE3 fusions unveils novel vulnerabilities in translocation renal cell carcinoma [RNA-Seq]

ABSTRACT: Metabolic reprogramming driven by TFE3 fusions unveils novel vulnerabilities in translocation renal cell carcinoma [RNA-Seq]

PROVIDER: PRJNA1107488 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

Metabolic reprogramming driven by TFE3 fusions unveils novel vulnerabilities in translocation renal cell carcinoma [RNA-Seq]

Project description:Translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer driven by TFE3 gene fusions, which act via poorly characterized downstream mechanisms. Here we report that TFE3 fusions transcriptionally rewire tRCCs toward oxidative phosphorylation (OXPHOS), contrasting with the highly glycolytic metabolism of most other RCCs. The transcriptional program driven by TFE3 fusions sustains high NRF2 signaling and glutathione production, which offsets reactive oxygen species generated by OXPHOS but renders tRCC cells sensitive to reductive stress. Genome-scale CRISPR screening identifies tRCC-selective vulnerabilities linked to maintaining this metabolic balance, including EGLN1, which hydroxylates HIF-1α and targets it for proteolysis. Inhibition of EGLN1compromises tRCC cell growth by stabilizing HIF-1a and promoting glycolytic reprogramming. Our study defines a distinctive tRCC-essential metabolic program driven by TFE3 fusions and nominates EGLN1inhibition as a therapeutic strategy to counteract fusion-induced metabolic rewiring.

2024-08-10 | GSE266517 | GEO

TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma

Project description:TFE3 is a member of the basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer. Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS) we interrogated a number of oncogenic mechanisms of TFE3-SF-containing fusions. We demonstrate that inhibition of TFE3-SF dimerization reverses its oncogenic activity and represents a potential new target for therapeutic intervention. Using HTHCS combined with FRET technology, we screened the FDA approved drugs library LOPAC and a small molecule library (Microsource) and identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D models utilizing patient derived xenolines and xenografts expressing TFE3-SF. The antihistamine terfenadine demonstrated decreased cell proliferation and reduced in vivo tumor growth. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.

2023-09-01 | GSE237407 | GEO

TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas.

Project description:ChIP analysis demonstrated that TFE3 fusions could bind to the promoters of the target genes as a wild-type TFE3 protein.

2024-05-15 | GSE267212 | GEO

TFE3 Xp11.2 translocation renal cell carcinoma mouse model

Project description:Renal Cell Carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization. To facilitate the development of molecular-based diagnostic tools and targeted therapies for TFE3-RCC, we generated a translocation RCC mouse model and performed DNA microarray analysis.

2019-04-20 | GSE130072 | GEO

TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma

Project description:TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma

| PRJNA994905 | ENA

DETECTION OF FOUR NOVEL RENAL TUMORS CASES HARBORING RBM10-TFE3 FUSIONS

Project description:Microphtalmia-associated-transcriptional-factor-family translocation renal cell carcinoma (MiTF-tRCC) currently includes two main subtypes: “TFEB-tRCC” most often characterized by a t(6;11)(p21;q13) that generates a fusion of TFEB with MALAT1 and “TFE3-tRCC” characterized by rearrangements of TFE3 at Xp11.23 (2-3) that produce a variety of fusion genes. FISH is a handy method in routine practice that allows the detection of a rearrangement of TFE3. However, it reaches its limits in cases of micro-inversions or insertions: in fact paracentric microinversions that involve GRIPAP1 (Xp11.23) (23, Classe) or RBM10 (Xp11.3), very close to TFE3 , are most often undetectable.We report the clinical, immunohistological, genomic and molecular description of four novel TFE3-tRCC with RBM10-TFE3 fusion detected by targeted RNASeq analysis that illustrate the difficulties of diagnosis, especially in reason of disconcerting negative TFE3 FISH results.

2020-11-04 | GSE160731 | GEO

TFE3 Xp11.2 translocation renal cell carcinoma mouse model

Project description:TFE3 Xp11.2 translocation renal cell carcinoma mouse model

| PRJNA533790 | ENA

DETECTION OF FOUR NOVEL RENAL TUMORS CASES HARBORING RBM10-TFE3 FUSIONS

Project description:DETECTION OF FOUR NOVEL RENAL TUMORS CASES HARBORING RBM10-TFE3 FUSIONS

| PRJNA674304 | ENA

TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas.

Project description:TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas.

| PRJNA1110249 | ENA

Genome-wide identification of oncogenic fusions in lung cancer by functional translocation sequencing

Project description:Fusions involving tyrosine kinases are oncogenic drivers in lung cancer and other solid tumors but also mediate resistance to targeted therapy. Despite gene rearrangements involving tyrosine kinases tending to show recurrent patterns in solid tumors, little is known about their mechanisms of formation and their selection process. To elucidate these mechanisms, we developed a functional high-throughput, genome-wide translocation sequencing (F-HTGTS) approach. We applied F-HTGTS to lung cancer cells under the selective pressure of EGFR inhibition to map genome-wide translocations when a DNA double-strand break occurs in the ALK, RET, ROS1 or NTRK1 tyrosine kinase. We found that translocations form spontaneously with several partners in the genome, generate functional fusion proteins and induce resistance to EGFR inhibitors. Several of these proteins reproduce precisely the fusions found in NSCLC patients either as original driver events or secondary to development of resistance to targeted therapy. Therefore, F-HTGTS is an approach that allows rapid and comprehensive mapping of tyrosine kinase fusions in the genome from common oncogenic kinases and provide insights on their mechanisms of formation.

2024-04-29 | GSE167155 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data