Epithelial tumor suppressor deletion promotes neuroendocrine differentiation in bladder cancer and reveals homoharringtonine as a candidate vulnerability.

Neuroendocrine bladder carcinoma (NEBC) is a highly aggressive malignancy with unresolved lineage determinants and limited preclinical models, hindering mechanistic investigation and therapeutic development. Here, we sought to assess whether bladder epithelial-derived models are competent to acquire neuroendocrine lineage programs under defined tumor suppressor alterations and to identify candidate therapeutic vulnerabilities in these systems. We integrated genomic and transcriptomic analyses of human NEBC with genetically engineered mouse models, epithelial-derived bladder organoids, and patient-derived NEBC models. Human NEBC exhibited dominant RB1 and TP53 alterations and an epithelial transcriptional continuum consistent with lineage plasticity. In vivo, intravesical Adeno-Cre-mediated tumor suppressor deletion predominantly generated sarcoma-like tumors, whereas epithelial-restricted organoid models recapitulated the molecular and neuroendocrine features of human NEBC, supporting epithelial lineage competence for neuroendocrine differentiation. Patient-derived models and human NEBC specimens further supported epithelial identity in NEBC. Using these complementary platforms, drug screening identified homoharringtonine (HHT) as a candidate therapeutic vulnerability in the tested NEBC systems. HHT suppressed neuroendocrine marker expression, induced apoptosis, and attenuated IL6-JAK-STAT3 signaling. Together, these findings describe complementary epithelial-derived NEBC models and support further investigation of HHT as a candidate therapeutic vulnerability.