Deciphering the Transcription Factor Landscape in Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

Yu Wang; Hui Xue; Xiaohui Zhu; Dong Lin; Zheng Chen; Xin Dong; Junru Chen; Mingchen Shi; Yuchao Ni; Jonathan Cao; Rebecca Wu; Connie Kang; Xinyao Pang; Francesco Crea; Yen-Yi Lin; Colin C Collins; Martin E Gleave; Abhijit Parolia; Arul Chinnaiyan; Christopher J Ong; Yuzhuo Wang

doi:10.1002/advs.202404938

Deciphering the Transcription Factor Landscape in Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

Adv Sci (Weinh). 2025 Mar 17:e2404938. doi: 10.1002/advs.202404938. Online ahead of print.

Authors

Yu Wang^{1

2

3}, Hui Xue³, Xiaohui Zhu⁴, Dong Lin^{2

3}, Zheng Chen⁴, Xin Dong³, Junru Chen⁵, Mingchen Shi^{1

2

3}, Yuchao Ni^{1

2

3

5}, Jonathan Cao⁶, Rebecca Wu³, Connie Kang³, Xinyao Pang^{1

2

3}, Francesco Crea⁷, Yen-Yi Lin^{1

2}, Colin C Collins^{1

2}, Martin E Gleave^{1

2}, Abhijit Parolia⁸, Arul Chinnaiyan⁸, Christopher J Ong^{1

2}, Yuzhuo Wang^{1

2

3}

Affiliations

¹ Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, V5Z 1M9, Canada.
² Vancouver Prostate Centre, Vancouver, V6H 3Z6, Canada.
³ Department of Experimental Therapeutics, BC Cancer, Vancouver, V5Z 1L3, Canada.
⁴ The First Affiliated Hospital of Jinan University, First Clinical Medical College, Jinan University, Guangzhou, 510632, P. R. China.
⁵ Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China.
⁶ Department of Cell and Systems Biology, University of Toronto, Toronto, M5S 3G5, Canada.
⁷ Cancer Research Group, School of Life Health and Chemical Sciences, The Open University, Milton Keynes, MK7 6AA, UK.
⁸ Michigan Center for Translational Pathology, Department of Urology, University of Michigan Medical School, Rogel Cancer Center, University of Michigan Hospital, Ann Arbor, 48109, USA.

PMID: 40091506
DOI: 10.1002/advs.202404938

Abstract

Prostate cancer (PCa) stands as a leading cause of cancer-related mortality among men, with treatment-induced neuroendocrine prostate cancer (NEPC) posing a challenge as an ARPI-resistant subtype. The role of transcription factors (TFs) in PCa progression and NEPC transdifferentiation remains inadequately understood, underscoring a critical gap in current research. In this study, an internal Z score-based approach is developed to identify lineage-specific TF profiles in prostatic adenocarcinoma and NEPC for a nuanced understanding of TF expression dynamics. Distinct TF profiles for adenocarcinoma and NEPC are unveiled, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs, validated across multiple cohorts. Gene Ontology is employed to validate their biological and functional roles in PCa progression. Implications are revealed in cell development, differentiation, and lineage determination. Knockdown experiments suggest that lineage-TFs are functionally important in maintaining lineage-specific cell proliferation. Additionally, a longitudinal study on NE transdifferentiation highlights dynamic TF expression shifts, proposing a three-phases hypothesis for PCa progression mechanisms. This study introduces a groundbreaking approach for deciphering the TF landscape in PCa, providing a molecular basis for adenocarcinoma to NEPC progression, and paving the way for innovative treatment strategies with potential impact on patient outcomes.

Keywords: De‐differentiation; NE transdifferentiation; adenocarcinoma; dormancy; lineage plasticity; neuroendocrine prostate cancer; transcription factor.

Abstract

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