An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC
Translocation renal cell carcinoma (tRCC) is a rare, aggressive kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members <i>TFE3</i> or <i>TFEB</i>. The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. We utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expressing one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion-expressing tubuloids adopt a tRCC-like phenotype and gene expression signature <i>in vitro</i> and grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis suggests that SFPQ-TFE3 reprograms gene expression signatures by widespread, aberrant DNA binding. Combining these analyses with single-cell mRNA readouts reveals a derailed epithelial differentiation trajectory that is at the root of transformation toward tRCC. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation.
Authors
- Susana M. Chuva de Sousa Lopes (ORCID: https://orcid.org/0000-0003-3866-2803)
- Aleksandra Balwierz (ORCID: https://orcid.org/0000-0002-5640-9839)
- Francisco Morales-Rodriguez
- Sepide Derakhshan
- Thanasis Margaritis (ORCID: https://orcid.org/0000-0003-4040-2015)
- Alexander van Oudenaarden (ORCID: https://orcid.org/0000-0002-9442-3551)
- Marry M. van den Heuvel‐Eibrink (ORCID: https://orcid.org/0000-0002-7760-879X)
- Jarno Drost (ORCID: https://orcid.org/0000-0002-2941-6179)
- Dilara Ayyildiz (ORCID: https://orcid.org/0000-0002-8627-4648)
- Nhung Pham (ORCID: https://orcid.org/0000-0003-3091-3962)
- Ronald R. de Krijger (ORCID: https://orcid.org/0000-0001-6871-1296)
- Philip Lijnzaad (ORCID: https://orcid.org/0000-0002-7535-583X)
- Maroussia M. P. Ganpat (ORCID: https://orcid.org/0009-0006-9935-5697)
- Peter Zeller (ORCID: https://orcid.org/0000-0003-2537-0254)
- Arianna Fumagalli (ORCID: https://orcid.org/0000-0002-3483-8026)
- Terezinha de Souza
Institutions
- Royal Netherlands Academy of Arts and Sciences (NL)
- Heidelberg University (DE)
- Leiden University Medical Center (NL)
- Ghent University Hospital (BE)
- University Hospital Heidelberg (DE)
- University Medical Center Utrecht (NL)
- Oncode Institute (NL)
- Princess Máxima Center (NL)
- Lygature (NL)
- Wilhelmina Children's Hospital (NL)
Publication Details
- Journal
- iScience
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.isci.2025.112122
- Citations
- 3
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 3.14
Funders
- American Association for Cancer Research
- St. Baldrick's Foundation
- KWF Kankerbestrijding
- Stichting Kinderen Kankervrij
- Oncode Institute
- H2020 European Research Council