Epigenetic regulation of Hedgehog-BMP signaling axis in the development and progression of human bladder cancer

Abstract

In bladder, loss of mammalian Sonic Hedgehog (Shh) accompanies progression to invasive urothelial carcinoma, but the molecular mechanisms underlying this cancer-initiating event are poorly defined. In chapter 2 and chapter 3, I show that loss of Shh results from hypermethylation of the CpG shore of the Shh gene, and that inhibition of DNA methylation increases Shh expression to halt the initiation of murine urothelial carcinoma at the early stage of progression. In full-fledged tumors, pharmacologic augmentation of Hedgehog (Hh) pathway activity impedes tumor growth, and this cancer-restraining effect of Hh signaling is mediated by the stromal response to Shh signals, which stimulates subtype conversion of basal to luminal-like urothelial carcinoma. These findings provide a basis that cancer-related processes and signaling pathways is the new therapeutic target for bladder cancer. To study this hypothesis in human, development of three-dimensional (3D) organ-like structures was an important issue. Current organoid models are limited by their failure to account for factors, such as tissue microenvironment. In chapter 4, multi-layered tumor organoids with stroma is developed that recapitulate the in vivo pathophysiology of patient-derived invasive urothelial carcinoma, including tumor–stroma interaction including anti-cancer effects of Hh signaling. Thus, this thesis provides a conceptual framework for the reconstitution of multi-layered, functional organoids to develop subtype-specific strategies for the management of human bladder cancer.