Epigenomic analyses of FOXA1-mediated enhancer reprogramming to control tumor subtype plasticity through HH-BMP-FOXA1 signalling feedback between urothelial tumor and stromal fibroblasts [ATAC-seq]

ABSTRACT: Consistent with the previous study, we showed that tumor molecular subtypes switched between the luminal subtype and the basal subtype during long-term maintenance of conventional tumor organoids in the absence of stroma in vitro, indicating the important role of tumor stroma in maintaining the tumor phenotype. Interestingly, genomic alterations seen in parental tumors are preserved well in both conventional tumor organoids and tumor assembloids, implying that the determination of tumor phenotypes may rely on epigenetic changes in tumor stroma-dependent ways, particularly through stromal BMP signals, elicited by Hh expression in tumor cells. We performed extensive epigenomic analyses including RNA-seq, ATAC-seq, and ChIP-seq with genetically manipulated tumor assembloids, in which genetic manipulations were applied independently to tumor organoids and tumor stroma in a combinatorial manner. Using this system, we identified FOXA1 as a master pioneering factor that drives enhancer reprogramming during the molecular switching of tumor subtypes. We have also obtained new evidence that FOXA1 is induced by stromal BMP signals and identified the HH-BMP-FOXA1 signaling feedback between urothelial tumors and stromal fibroblasts as a critical signaling axis in the FOXA1-mediated enhancer reprogramming of tumor phenotypes in the determination of urothelial carcinomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141351 | GEO | 2020/09/27

REPOSITORIES: GEO