Related Experiment Video

Updated: Jan 17, 2026

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
06:38

A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies

Published on: April 12, 2017

14.1K

Fusion-driven oncogenic programs shape the immune landscape in translocation renal cell carcinoma

Prathyusha Konda, Cary N Weiss, Yantong Cui

    Biorxiv : the Preprint Server for Biology
    |September 15, 2025
    PubMed

    Insights

    Translocation renal cell carcinoma (tRCC) has distinct biology from clear cell RCC, featuring unique oncogenic programs and an immunosuppressive tumor microenvironment. Understanding tRCC

    Area of Science:

    • Oncology
    • Genetics
    • Immunology

    Background:

    • Renal cell carcinomas (RCCs) are molecularly diverse but often treated empirically due to poor understanding of subtype-specific biology.
    • Clear cell RCC (ccRCC) is the most common subtype, and current therapies are primarily designed for it.
    • Translocation RCC (tRCC), defined by TFE3 gene fusions, is an aggressive subtype with unclear biological drivers.

    Purpose of the Study:

    • To investigate the distinct molecular and cellular features of translocation renal cell carcinoma (tRCC).
    • To understand the oncogenic programs and tumor microenvironment (TME) specific to tRCC.
    • To identify potential therapeutic strategies based on tRCC-specific biology.

    Main Methods:

    • Analysis of single-cell transcriptomes from tRCC tumors.
    • Chromatin accessibility profiling of tRCC.
    • Comparative analysis with ccRCC to identify subtype-specific differences.

    Main Results:

    • tRCCs exhibit distinct oncogenic programs and a markedly immunosuppressive TME, despite a similar cell of origin as ccRCC.
    • Six conserved tumor meta-programs were identified in tRCC, including epithelial-mesenchymal transition (EMT) and proximal tubule identity programs.
    • TFE3 fusion activity regulates the balance of these programs, driving an EMT program associated with exhausted CD8+ T cells, SPP1+ macrophages, and matrix-associated fibroblasts (mCAFs).

    Conclusions:

    • tRCC possesses unique TFE3 fusion-driven biology that differs significantly from ccRCC.
    • The identified oncogenic programs and immunosuppressive TME in tRCC explain its reduced responsiveness to immunotherapy compared to ccRCC.
    • Targeting fusion-driven oncogenic programs and reprogramming the tRCC TME are potential therapeutic avenues.

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