Targeting TPX2-dependent lineage plasticity by CDK4/6 inhibition reverses therapy resistance in neuroendocrine bladder carcinoma
Year: 2026
Type: article
Abstract: Neuroendocrine bladder carcinoma (NEBC) is an aggressive and therapy-resistant cancer with poor prognosis. Although lineage plasticity drives urothelial-to-neuroendocrine transdifferentiation, intermediate states remain poorly characterized. Through transcriptomic profiling of public datasets, we define a lineage plasticity-associated signature in bladder cancer. We analyze 64,756 in-house and 201,720 public single-cell transcriptomes from NEBC and urothelial carcinoma (UC), identifying TPX2 high bladder cancer cell subpopulation with increased lineage plasticity, supported by multi-cohort histological validation. TPX2 high cells lack canonical neuroendocrine markers and are associated with adverse clinical outcomes. TPX2 high cells exhibit dysregulated cell cycle progression and occupy a suppressive niche associated with CD8 + T cell exhaustion. In vitro and in vivo , TPX2 promotes lineage plasticity and induces T cell exhaustion. In preclinical patient-derived organoids (PDOs) and patient-derived xenograft (PDX) models, CDK4/6 inhibition plus immune checkpoint blockade demonstrates potent antitumor efficacy. Overall, our findings suggest this combination therapy as a promising therapeutic strategy for TPX2 high and NEBC patients.
Source: Cell Reports Medicine
Authors: Zehua Chen, Shengmeng Peng, Shi Fu, Shizhi Lin, Yiwen Su, Xinxin He, Yangjie Zhang, Junlin Lu, Sen Liu, Hengji Zhan, Jianmei Zhong, Baolin Ye, Chengjunyu Zhang, Chu Liu, Bolin Pan, Haonan Dong, Hongqiong Li, Xinni Ye, Jun Wang, Siting Chen, Baoqing He, Jingdie Wu, Hui Li, Qiang Zhang, Haifeng Wang, Xu Chen
Institutions: Sun Yat-sen University, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Kunming Medical University, Third Affiliated Hospital of Sun Yat-sen University, University of Virginia, Second Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Second Affiliated Hospital of Kunming Medical College
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Natural Science Foundation of China, Ministry of Science and Technology of the People's Republic of China, Guangdong Science and Technology Department, Yunnan Provincial Science and Technology Department, People's Government of Yunnan Province, Guangzhou Municipal Science and Technology Bureau
OpenAlex ID: W7147095871