Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation.
A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation.
unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression.
The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.
bioRxiv : the preprint server for biology. 2024 Apr 29*** epublish ***
Yu Wang, Hui Xue, Xiaohui Zhu, Dong Lin, Xin Dong, Zheng Chen, Junru Chen, Mingchen Shi, Yuchao Ni, Jonathan Cao, Rebecca Wu, Ning Kang, Xinyao Pang, Francesco Crea, Yen-Yi Lin, Colin C Collins, Martin E Gleave, Abhijit Parolia, Arul Chinnaiyan, Christopher J Ong, Yuzhuo Wang