An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC

Maroussia M P Ganpat; Francisco Morales-Rodriguez; Nhung Pham; Philip Lijnzaad; Terezinha de Souza; Sepide Derakhshan; Arianna Fumagalli; Peter Zeller; Aleksandra Balwierz; Dilara Ayyildiz; Marry M van den Heuvel-Eibrink; Ronald R de Krijger; Alexander van Oudenaarden; Thanasis Margaritis; Susana M Chuva de Sousa Lopes; Jarno Drost

doi:10.1016/j.isci.2025.112122

An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC

iScience. 2025 Mar 1;28(4):112122. doi: 10.1016/j.isci.2025.112122. eCollection 2025 Apr 18.

Authors

Maroussia M P Ganpat^{1

2}, Francisco Morales-Rodriguez^{1

2}, Nhung Pham^{1

2}, Philip Lijnzaad¹, Terezinha de Souza^{1

2}, Sepide Derakhshan^{1

2}, Arianna Fumagalli^{1

2}, Peter Zeller^{2

3

4}, Aleksandra Balwierz¹, Dilara Ayyildiz^{1

2}, Marry M van den Heuvel-Eibrink^{1

5}, Ronald R de Krijger^{1

6}, Alexander van Oudenaarden^{2

3

4}, Thanasis Margaritis¹, Susana M Chuva de Sousa Lopes^{7

8}, Jarno Drost^{1

2}

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, Utrecht 3584 CS, the Netherlands.
² Oncode Institute, Jaarbeursplein 6, Utrecht 3521 AL, the Netherlands.
³ Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Science), Uppsalalaan 8, Utrecht 3584 CT, the Netherlands.
⁴ University Medical Center, Heidelberglaan 100, Utrecht 3584 CX, the Netherlands.
⁵ Division of Child Health, Wilhelmina Children's Hospital, Heidelberglaan 100, Utrecht 3584 CX, the Netherlands.
⁶ Department of Pathology, University Medical Center, Heidelberglaan 100, Utrecht 3584 CX, the Netherlands.
⁷ Department of Anatomy and Embryology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, the Netherlands.
⁸ Department of Reproductive Medicine, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium.

Abstract

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 TFE3 or TFEB. 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 in vitro 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.

Keywords: Bioengineering; Natural sciences; biological sciences; tissue engineering.