Genetically engineered human iPS cell-derived kidney organoid recapitulates an early stage of ALK fusion gene-associated renal tumorigenesis

Abstract 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.