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 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
- Wenchen Gong (ORCID: https://orcid.org/0000-0002-7637-3538)
- Zhiqun Shang (ORCID: https://orcid.org/0000-0001-8263-707X)
- Zhang Zd
- Zhe Liu (ORCID: https://orcid.org/0000-0002-2536-4180)
- Wenxu Liu (ORCID: https://orcid.org/0000-0002-1647-9162)
- Luc Girard (ORCID: https://orcid.org/0000-0002-6688-5281)
- Lance S. Terada (ORCID: https://orcid.org/0000-0001-7441-9734)
- John D. Minna (ORCID: https://orcid.org/0000-0002-7776-0767)
- Zhenyi Ma (ORCID: https://orcid.org/0000-0001-6962-2711)
- Junrong Liu (ORCID: https://orcid.org/0000-0002-3920-6773)
- Lin Wang (ORCID: https://orcid.org/0000-0001-5716-6587)
- Jun Yan (ORCID: https://orcid.org/0000-0002-3261-0749)
- Jin Yan (ORCID: https://orcid.org/0009-0002-1828-4817)
- Xuemiao Yan
- X Chen
- Benjamin J. Drapkin
- Yuanjie Niu
- Yuan Jiang
- Ailing Wu
- Yujie Hao
Institutions
- Hangzhou Normal University (CN)
- Tianjin First Center Hospital (CN)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Affiliated Hospital of Hangzhou Normal University (CN)
- Second Hospital of Tianjin Medical University (CN)
- Tianjin Medical University (CN)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-07-23
- DOI
- https://doi.org/10.1172/jci190596
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Prevention and Research Institute of Texas
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Jinan University
- Hangzhou Normal University
- National Institutes of Health