Integrative Single Cell Atlas Revealed Intratumoral Heterogeneity Generation from an Adaptive Epigenetic Cell State in Human Bladder Urothelial Carcinoma.
Yu XiaoWan JinKaiyu QianLingao JuGang WangKai WuRui CaoLuyuan ChangZilin XuJun LuoLiuying ShanFang YuXintong ChenDongmei LiuHong CaoYejinpeng WangXinyue CaoWei ZhouDiansheng CuiYe TianChundong JiYongwen LuoXin HongFangjin ChenMinsheng PengYi ZhangXing-Huan WangPublished in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2024)
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.
Keyphrases
- single cell
- low grade
- high grade
- rna seq
- stem cells
- poor prognosis
- dna methylation
- papillary thyroid
- high throughput
- gene expression
- genome wide
- long non coding rna
- squamous cell
- transcription factor
- endothelial cells
- induced apoptosis
- risk factors
- cell therapy
- lymph node metastasis
- squamous cell carcinoma
- cell cycle arrest
- childhood cancer
- network analysis
- binding protein
- heat shock protein
- data analysis
- urinary tract
- endoplasmic reticulum stress
- replacement therapy