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

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 mouse adenocarcinomas and in LNCAP prostate cancer xenografts induced 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 an 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 small cell neuroendocrine carcinoma and adenocarcinomas.