TFE3 Xp11.2 translocation renal cell carcinoma mouse model
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ABSTRACT:
PROVIDER: PRJNA533790 | ENA |
REPOSITORIES: ENA
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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
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
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.
2024-12-30 | GSE266530 | GEO
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
Project description:The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterised. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos) increasing functional OxPhos levels. Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). EMT of tRCC tumours was further associated with presence of mesenchymal tRCC cancer cells and myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We provide unique insights into how broad genomic binding of TFE3 fusion proteins promotes tRCC tumourigenesis by regulating OxPhos and ferroptosis resistance and more generally stimulating RNA synthesis.
2025-02-01 | GSE268092 | GEO
Project description:Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto unreported SFPQ-TFEB fusion) and a variety of tumorgraft models (ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3, and MALAT1-TFEB) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research
2024-01-04 | GSE252047 | GEO
Project description:Next generation sequencing of TFE3-translocation renal cell carcinoma and adjacent normal tissue transcriptomes
| PRJNA704974 | ENA
Project description:The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterised. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos) increasing functional OxPhos levels. Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). EMT of tRCC tumours was further associated with presence of mesenchymal tRCC cancer cells and myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We provide unique insights into how broad genomic binding of TFE3 fusion proteins promotes tRCC tumourigenesis by regulating OxPhos and ferroptosis resistance and more generally stimulating RNA synthesis.
2025-02-01 | GSE268089 | GEO
Project description:PRCC-TFE3 is an oncogenic chimeric transcription factor identified in human TFE3-rearranged renal cell carcinoma. To investigate the function of PRCC-TFE3 in vivo, we generated PRCC-TFE3 knock-in (KI) mice by inserting a loxP-STOP-loxP-PRCC-TFE3 cassette into the Rosa26 locus. When PRCC-TFE3 KI mice were crossed with Cadherin 16-Cre transgenic mice (KSP-Cre), the resulting mice developed TFE3-RCC in the kidney. Our findings revealed that hypoxia-inducible factors HIF1α and HIF2α are directly upregulated by PRCC-TFE3. To clarify the roles of HIF1α and HIF2α in TFE3-RCC development, we further crossed PRCC-TFE3 KI mice with HIF1α flox and/or HIF2α flox mice.
2025-01-07 | GSE283743 | GEO
Project description:TFE3-splicing factor fusions represent functional drivers and druggable targets in translocation renal cell carcinoma
| PRJNA994905 | ENA