Integrative Single Cell Atlas Revealed Intratumoral Heterogeneity Generation from an Adaptive Epigenetic Cell State in Human Bladder Urothelial Carcinoma
Yu Xiao, Wan Jin, Kaiyu Qian, Lingao Ju, Gang Wang, Kaichun Wu, Rui Cao, Luyuan Chang, Zilin Xu, Jun Luo, Liuying Shan, Fang Yu, Xintong Chen, Dongmei Liu, Hong Cao, Yejinpeng Wang, Xinyue Cao, Wei Zhou, Diansheng Cui, Ye Tian, Chundong Ji, Yongwen Luo, Xin Hong, Fangjin Chen, Min‐Sheng Peng, Yi Zhang, Xinghuan Wang
Abstract
Intratumor heterogeneity (ITH) of bladder cancer (BLCA) contributes to therapy resistance and immune evasion affecting clinical prognosis. The molecular and cellular mechanisms contributing to BLCA ITH generation remain elusive. It is found that a TM4SF1-positive cancer subpopulation (TPCS) can generate ITH in BLCA, evidenced by integrative single cell atlas analysis. Extensive profiling of the epigenome and transcriptome of all stages of BLCA revealed their evolutionary trajectories. Distinct ancestor cells gave rise to low-grade noninvasive and high-grade invasive BLCA. Epigenome reprograming led to transcriptional heterogeneity in BLCA. During early oncogenesis, epithelial-to-mesenchymal transition generated TPCS. TPCS has stem-cell-like properties and exhibited transcriptional plasticity, priming the development of transcriptionally heterogeneous descendent cell lineages. Moreover, TPCS prevalence in tumor is associated with advanced stage cancer and poor prognosis. The results of this study suggested that bladder cancer interacts with its environment by acquiring a stem cell-like epigenomic landscape, which might generate ITH without additional genetic diversification.