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The molecular and cellular mechanisms contributing to BLCA ITH generation remain elusive. It is found that a TM4SF1\u2010positive 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\u2010grade noninvasive and high\u2010grade invasive BLCA. Epigenome reprograming led to transcriptional heterogeneity in BLCA. During early oncogenesis, epithelial\u2010to\u2010mesenchymal transition generated TPCS. TPCS has stem\u2010cell\u2010like 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\u2010like epigenomic landscape, which might generate ITH without additional genetic diversification.<\/jats:p>","DOI":"10.1002\/advs.202308438","type":"journal-article","created":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T19:30:16Z","timestamp":1712431816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Integrative Single Cell Atlas Revealed Intratumoral Heterogeneity Generation from an Adaptive Epigenetic Cell State in Human Bladder Urothelial Carcinoma"],"prefix":"10.1002","volume":"11","author":[{"given":"Yu","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Urology, Hubei Key Laboratory of Urological Diseases, Department of Biological Repositories, Human Genetic Resources Preservation Center of Hubei Province Zhongnan Hospital of Wuhan University  Wuhan 430071 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