Eunjee Kim1, Seoyoung Choi1, Byunghee Kang1,2, JungHo Kong1, Yubin Kim1, Woong Hee Yoon2, Hwa-Rim Lee3, SungEun Kim1, Hyo-Min Kim1,2, HyeSun Lee4, Chorong Yang2, You Jeong Lee2, Minyong Kang5,6,7, Tae-Young Roh1,2,*, Sungjune Jung2,3, Sanguk Kim1, Ja Hyeon Ku4,* & Kunyoo Shin1,*
1Department of Life Sciences, Pohang University of Science and Technology, Pohang, South Korea. 2Department of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, South Korea. 3Department of Creative IT Engineering, Pohang University of Science and Technology, Pohang, South Korea. 4Department of Urology, Seoul National University Hospital, Seoul, South Korea. 5Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 6Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea. 7Department of Digital Health, SAIHST, Sungkyunkwan University, Seoul, South Korea.
*Correspondence to Tae-Young Roh or Ja Hyeon Ku or Kunyoo Shin.
Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments. 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.