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. Cancer relapses after chemotherapy remain the primary challenge in cancer treatment. Here, authors show that bladder tumours recur from quiescent epidermoid-like cells and map how these cells evolve under treatment, identifying insulin-like growth factorbinding protein 5 as a potential target to curb chemoresistance and progression.