Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments1,2. Here we create multilayer bladder ‘assembloids’ by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1–BMP–hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.
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Acknowledgements We thank I. Weissman at Stanford University for their generous provision of the Rainbow mouse. This research was supported by grants from the National Research Foundation of Korea (NRF-2020R1A2B5B01001490, NRF-2017M3C7A104787521, NRF-2017R1A5A101536614 and NRF-2014M3C9A3064548), Gyeongbuk Science and Technology Promotion Center of Korea (SF317001A), POSCO (2018Y060), and the BK21 Plus and BK21 FOUR Research Fellowship.
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