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

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

PROVIDER: PRJNA994905 | ENA |

REPOSITORIES: ENA

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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

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 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.

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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.

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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.

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis[RNASeq]

Project description:Several different YAP1 gene fusions have been identified in various human cancers. We performed RNA sequencing on human neural stem cells overexpressing either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3, as well as on whole tumor lysates from mouse brain tumors generated by intra-cranial expression of either YAP1-MAMLD1, YAP1-FAM118B, or YAP1-TFE3.

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Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis [mouse RNA-seq]

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