Abstract
Human carcinomas often gain aggressive characteristics and escape cell-type specific treatment regimens through cryptic shifts in lineage states. However, the underlying mechanisms that govern lineage plasticity in carcinomas are undefined. Here in this study, we found that PAX5, a neural/lymphatic transcription factor, contributed to neuroendocrine (NE) lineage transition. PAX5 was highly expressed in aggressive human NE carcinoma cells and tissues but not in non-NE cancer cells and tissues. Deletion of Pax5 in Rb1fl/fl;Trp53fl/fl mice caused a reduction of tumor vessels, loss of NE morphologic features and decreased expression of ASCL1, NCAM, and SYP, whereas ectopic expression of PAX5 in CC10-rtTA;TetO-hEGFRex19del/T790M mice adenocarcinomas and in LNCAP prostate cancer xenografts induces an angiogenic microenvironment and NE morphology. Importantly, antiangiogenic drugs reduced NE features of Rb1fl/fl;Trp53fl/fl tumors and blocked PAX5-induced NE transformation. These studies demonstrate an essential role of angiogenic microenvironment in transition/maintenance of NE lineage, suggesting that targeting PAX5 and its downstream signaling may modulate lineage transitions responsible for treatment failure in both SCNCs and adenocarcinomas.
Authors
Ailing Wu, Yujie Hao, Xuemiao Yan, Junrong Liu, Lin Wang, Yan Jin, Wenxu Liu, Xiyue Chen, Yuan Jiang, Luc Girard, Zhiqun Shang, Jun Yan, Zhenfa Zhang, Wenchen Gong, Yuanjie Niu, Benjamin J. Drapkin, John D. Minna, Lance S. Terada, Zhenyi Ma, Zhe Liu
Graphical abstract
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)