PAX5 modulates vascularization and contributes to neuroendocrine lineage transition during carcinoma progression

作者：Ailing Wu, Yujie Hao, Xuemiao Yan, Junrong Liu, Lin Wang, Jin Yan, Wenxu Liu, X Chen, Yuan Jiang, Luc Girard, Zhiqun Shang, Jun Yan, Zhang Zd, Wenchen Gong, Yuanjie Niu, Benjamin J. Drapkin, John D. Minna, Lance S. Terada, Zhenyi Ma, Zhe Liu · 发表于：Journal of Clinical Investigation · 年份：2026 · DOI：10.1172/jci190596 · 研究领域：Cancer Cells and Metastasis、Angiogenesis and VEGF in Cancer、Neuroendocrine Tumor Research Advances

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.