| 描述信息 |
Neuroendocrine bladder carcinoma (NEBC) is an aggressive and therapy-resistant subtype with a poor prognosis. Although lineage plasticity is known to drive urothelial-to-neuroendocrine transdifferentiation, the intermediate states and their role in disease progression remain poorly characterized. Here, through integrated bulk and single-cell transcriptomic analyses of 2745 bladder cancer samples, we identify a distinct, transcriptionally plastic tumor subpopulation that lacks canonical neuroendocrine markers but is enriched for lineage plasticity programs.This subpopulation, characterized by high expression of TPX2, is associated with adverse clinical outcomes and localized to immune-desert regions within the tumor microenvironment (TME). We further demonstrate that these TPX2high cells exhibit dysregulated cell cycle progression, specifically G1/S phase enrichment, and are closely associated with CD8 T-cell exhaustion, indicating early immune evasion. Functional studies confirm that TPX2 accelerates the G1/S transition and promotes neuroendocrine differentiation. Importantly, pharmacological inhibition of CDK46 a key downstream target exerts potent antitumor effects in both patient-derived organoid and xenograft models of NEBC. Our findings define TPX2high cells as a critical transitional state within the lineage plasticity continuum and reveal cell cycle dysregulation as a targetable vulnerability in NEBC. These results provide a mechanistic basis for combining CDK4/6 inhibitors with immune checkpoint blockade to overcome therapy resistance in this lethal malignancy. |
