دورية أكاديمية
Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis.
| العنوان: | Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis. |
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| المؤلفون: | Prakasam G; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Mishra A; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Christie A; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Peter O' Donnell Jr. School of Public Health., Miyata J; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Carrillo D; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Tcheuyap VT; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Ye H; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Do QN; Department of Radiology, and., Wang Y; Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Reig Torras O; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Department of Medical Oncology and Translational Genomics and Targeted Therapies in Solid Tumors, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain., Butti R; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Zhong H; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Gagan J; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Jones KB; Department of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA., Carroll TJ; Department of Molecular Biology and Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Modrusan Z; Department of Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing and., Durinck S; Department of Oncology Bioinformatics, Genentech Inc., South San Francisco, California, USA., Requena-Komuro MC; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine., Williams NS; Department of Biochemistry., Pedrosa I; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Department of Radiology, and.; Advanced Imaging Research Center, and.; Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Wang T; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Peter O' Donnell Jr. School of Public Health.; Quantitative Biomedical Research Center, Department of Population and Data Sciences, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Rakheja D; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Kapur P; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.; Department of Urology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Brugarolas J; Kidney Cancer Program, Simmons Comprehensive Cancer Center.; Hematology-Oncology Division, Department of Internal Medicine. |
| المصدر: | The Journal of clinical investigation [J Clin Invest] 2024 Feb 22; Vol. 134 (7). Date of Electronic Publication: 2024 Feb 22. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation Original Publication: New Haven [etc.] American Society for Clinical Investigation. |
| مواضيع طبية MeSH: | Carcinoma, Renal Cell*/pathology , Kidney Neoplasms*/pathology, Animals ; Mice ; Infant, Newborn ; Humans ; Carcinogenesis/genetics ; Cell Transformation, Neoplastic/genetics ; Disease Models, Animal ; Transcription Factors/genetics ; Genomics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Translocation, Genetic ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; RNA-Binding Proteins/genetics |
| مستخلص: | 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. |
| معلومات مُعتمدة: | K25 HD104004 United States HD NICHD NIH HHS; P30 CA142543 United States CA NCI NIH HHS; P50 CA196516 United States CA NCI NIH HHS; R21 CA263264 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: Cancer; Cell biology; Molecular genetics; Mouse models; Oncology |
| المشرفين على المادة: | 0 (Transcription Factors) 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) 0 (Oncogene Proteins, Fusion) 0 (RBM10 protein, human) 0 (RNA-Binding Proteins) |
| تواريخ الأحداث: | Date Created: 20240222 Date Completed: 20240403 Latest Revision: 20240430 |
| رمز التحديث: | 20240430 |
| مُعرف محوري في PubMed: | PMC10977987 |
| DOI: | 10.1172/JCI170559 |
| PMID: | 38386415 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1558-8238 |
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| DOI: | 10.1172/JCI170559 |