Recurrence in the chemotherapy regimen of bladder carcinoma originates from quiescent epidermoid-like cells.

Cancer relapse upon chemotherapy remains the primary challenge in cancer treatment. By integrating high-resolution CRISPR/Cas9-based evolving lineage tracing with single-cell RNA sequencing in mice, we track the evolution of bladder carcinoma in the presence or absence of chemotherapy. We find that a cell population exhibiting an epidermoid-like cell state can survives chemotherapy. These epidermoid-like cells leave the quiescent state to initiate relapse, generating histologically distinct tumours through different evolutionary routes involving specific transcriptional changes. The plasticity of epidermoid-like cells and alterations in plasticity patterns during evolution shape the phenotypes of relapsed tumours. Integrated analyses reveal that Insulin-like growth factor-binding protein 5 is a key co-regulator of aggressive progression and squamous features in bladder carcinoma. Impeding insulin-like growth factor-binding protein 5 expression suppresses the chemoresistance and malignant behaviours of relapsed tumours. Our study deciphers key events and evolutionary dynamics during the natural progression and recurrence of bladder carcinoma. It offers a viable therapeutic approach to overcome the refractoriness of relapsed bladder carcinoma to conventional chemotherapy.