Genetically Engineered Human iPS Cell-Derived Kidney Organoid Recapitulates an Early Stage of <i>ALK</i> Fusion Gene-Associated Renal Tumorigenesis
Although kidney cancer arises from a variety of nephron cells with diverse characteristics and develops intra-tumor heterogeneity, a model to elucidate these complexities is incompletely developed. Here, we report a genetically engineered human iPS cell-derived kidney organoid (HKO) model, which may recapitulate an early stage of renal tumorigenesis. When we overexpressed VCL-ALK fusion gene, a renal oncogene, in HKO, tubular cells proliferated and this proliferation was sustained under long-term culture or hypoxic conditions. In addition, the proliferating tubular cells migrated into the renal parenchyma of host mice upon transplantation. The deconvolution analysis and immunohistochemistry revealed that proliferating tubular cells could be arrested at an immature tubular progenitor stage with increased expressions of LHX1 and JAG1, critical regulators of nephrogenesis. Our HKO model advances our understanding of renal tumorigenesis in the context of the trajectory of nephron development. Implications: Dysregulated nephron developmental machinery leads to aberrant cell proliferations of immature renal tubules.
Authors
- Mitsuko Furuya (ORCID: https://orcid.org/0000-0002-6220-8179)
- Shinji Ohtake (ORCID: https://orcid.org/0000-0003-3532-1034)
- Mitsuru Komeya (ORCID: https://orcid.org/0000-0002-0744-7492)
- Shohei Kuraoka (ORCID: https://orcid.org/0000-0003-1599-5162)
- Toyonori Tsuzuki (ORCID: https://orcid.org/0000-0002-4855-4366)
- Hiroki Ito (ORCID: https://orcid.org/0000-0002-4433-370X)
- Hidekazu Nishizawa (ORCID: https://orcid.org/0000-0001-9315-6650)
- Toshio Suda
- Hisashi Hasumi (ORCID: https://orcid.org/0000-0001-8211-8835)
- Yasuhiro Iribe
- Nobuhisa Mizuki (ORCID: https://orcid.org/0000-0003-3738-8777)
- Ryosuke Jikuya (ORCID: https://orcid.org/0000-0002-3446-6293)
- Tatsukata Kawagoe
- Go Noguchi (ORCID: https://orcid.org/0000-0003-4360-0391)
- Tomoyuki Tatenuma (ORCID: https://orcid.org/0000-0002-1908-4975)
- Taku Mitome (ORCID: https://orcid.org/0000-0002-0959-7312)
- Yoji Nagashima (ORCID: https://orcid.org/0000-0001-6691-7346)
- Kota Aomori
- Daiki Ueno (ORCID: https://orcid.org/0009-0002-3574-4264)
- Erika Muraoka
- Shintaro Funasaki
- Satoshi Fujii (ORCID: https://orcid.org/0000-0003-2818-5548)
- Sachi Kawaura
- Tomohiko Tamura (ORCID: https://orcid.org/0000-0002-9664-1747)
- Hidewaki Nakagawa
- KAZUHIDE MAKIYAMA
- Hiroji Uemura
- Hirotaka Nagasaka
- Brian M. Shuch
- W. Marston Linehan
- Takehiko Ogawa
- Masahiro Yao
- Kentaro Muraoka
- Laura S. Schmidt
- Christopher J. Ricketts
- Ikuma Kato
- Krisna Wilan
- Takashi Kawahara
- Yusuke Ito
- Ryuichi Nishinakamura
- Masaya Baba
- Tomomi Kamba
Institutions
- UCLA Health (US)
- Yokohama City University Medical Center (JP)
- Aichi Medical University Hospital (JP)
- Frederick National Laboratory for Cancer Research (US)
- Tokyo Women's Medical University Adachi Medical Center (JP)
- Tokyo Women's Medical University (JP)
- National Cancer Institute (US)
- Hokkaido University Hospital (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- Kumamoto Industrial Research Institute (JP)
- Yokohama City University (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Molecular Cancer Research
- Published
- 2025-12-22
- DOI
- https://doi.org/10.1158/1541-7786.mcr-25-0043
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 0.00