Comparative Genomics Incorporating Translocation Renal Cell Carcinoma Mouse Model Reveals Molecular Mechanisms of Tumorigenesis

Authors

Gopinath Prakasam
Akhilesh Mishra
Alana Christie
Jeffrey Miyata
Deyssy Carrillo
Vanina T Tcheuyap
Hui Ye
Quyen N Do
Yunguan Wang
Oscar Reig Torras
Ramesh Butti
Hua Zhong
Jeffrey Gagan
Kevin B Jones
Thomas J Carroll
Zora Modrusan
Steffen Durinck
Mai-Carmen Requena-Komuro
Noelle S Williams
Ivan Pedrosa
Tao Wang
Dinesh Rakheja
Payal Kapur
James Brugarolas

Language

English

Publication Date

2-22-2024

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI170559

PMID

38386415

PMCID

PMC10977987

PubMedCentral® Posted Date

2-22-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Mice, Infant, Newborn, Humans, Carcinoma, Renal Cell, Carcinogenesis, Cell Transformation, Neoplastic, Disease Models, Animal, Transcription Factors, Genomics, Kidney Neoplasms, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Mechanistic Target of Rapamycin Complex 1, Translocation, Genetic, Oncogene Proteins, Fusion, RNA-Binding Proteins

Published Open-Access

yes

Recommended Citation

Prakasam, Gopinath; Mishra, Akhilesh; Christie, Alana; et al., "Comparative Genomics Incorporating Translocation Renal Cell Carcinoma Mouse Model Reveals Molecular Mechanisms of Tumorigenesis" (2024). Faculty, Staff and Student Publications. 6403.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6403