Epigenetic evolution of bladder cancer from cellular origin to clinical translation

Abstract Background Bladder cancer remains difficult to manage because of extensive intratumoral heterogeneity, frequent recurrence, and variable response to standard treatment. The conventional view, which centres on the progressive accumulation of genetic mutations, does not adequately explain how tumours adapt under therapeutic pressure or why clinically distinct subtypes emerge from a shared urothelial origin. Recent single‐cell and epigenomic studies indicate that cellular plasticity and chromatin reprogramming substantially shape disease behaviour, prompting a reassessment of how progression and resistance should be modelled. Methods This mini‐review synthesises recent work that combines single‐cell chromatin accessibility profiling, DNA methylation analysis, and computational lineage inference to dissect the cellular origins and evolutionary trajectories of bladder cancer. We examine evidence that muscle‐invasive and non‐muscle‐invasive disease may arise from distinct urothelial cell populations, and that a TM4SF1‐positive cancer subpopulation acts as a stem‐like reservoir contributing to phenotypic diversification, therapeutic resistance, and metastatic competence. We then describe the molecular machinery proposed to sustain this plastic cell state, including androgen receptor and FOXA1 cooperation in enhancer remodelling, the conceptual separation of driver and passenger differentially methylated regions, and the POLD1 to MYC axis that stabilises oncogenic transcription. We further examine two translational outputs that have been built on this mechanistic foundation: a urine tumour DNA methylation assay developed for non‐invasive detection, risk stratification, and postoperative surveillance, and a conditionally reprogrammed cell platform that supports patient‐derived ex vivo drug sensitivity screening across urological cancers. Conclusion Framing bladder cancer as an epigenetically driven evolutionary process helps explain how heterogeneity arises and persists, and identifies clinically useful tools that complement existing genetic and pathological approaches. Prospective multi‐institutional validation of the urine methylation assay, panel refinement to improve sensitivity in low‐grade disease, and outcome‐linked drug sensitivity studies based on conditionally reprogrammed cells will determine the extent to which this framework can inform precision oncology in bladder cancer and serve as a template for other epithelial malignancies.