Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis
Gopinath Prakasam, … , Payal Kapur, James Brugarolas
Gopinath Prakasam, … , Payal Kapur, James Brugarolas
Published February 22, 2024
Citation Information: J Clin Invest. 2024;134(7):e170559. https://doi.org/10.1172/JCI170559.
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Research Article Cell biology Oncology

Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis

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.

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

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Figure 5

Comparative transcriptomic analyses of murine and human tRCC.

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Comparative transcriptomic analyses of murine and human tRCC. (A) Princi...
(A) Principal component analysis (PCA) representation of normalized gene expression read counts of kidney tumors (KT), retro-orbital tumors (ROT), intracranial brain tumors (BT), and non-tumor kidney (NTK) from Sglt2-Cre; ASPSCR1-TFE3LSL/+ mice (or adult Sglt2-Cre kidney controls) as well as deformed kidneys from Pax8-Cre; ASPSCR1-TFE3LSL/+ fetuses and fetal kidney controls (Pax8-Cre). (B) GSEA for Hallmark or KEGG gene signatures exhibiting top upregulated and downregulated pathways enriched in murine and human tRCC. NES, normalized enrichment score; FDR, false discovery rate. (C) PCA plot representation of normalized gene expression read counts for the UTSW pan-RCC cohort — tRCC (n = 19), clear cell RCC (ccRCC) (n = 193), papillary RCC (pRCC) (n = 55), and chromophobe RCC (chRCC) (n = 43) — and tumor-matched normal kidney (n = 179). (D) Venn diagram of significantly upregulated genes in human and murine tRCC. (E) Venn diagram of significantly downregulated genes in human and murine tRCC. (F) Venn diagram of SFPQ-TFE3 and NONO-TFE3 direct target genes from 2 independent ChIP-Seq studies. (G) Venn diagram of significantly upregulated genes in human/mouse tRCC and their interaction with shared (SFPQ-TFE3 and NONO-TFE3) direct target genes. Hypergeometric tests were carried out to test the overlap between gene expression signatures (D, E, and G). (H and I) Volcano plots of differentially expressed genes in human (H) and murine (I) tRCC. Green, downregulated genes; red, upregulated genes; gray, unchanged genes. Putative direct targets of MiT/TFE fusion protein are marked.