Poster Presentation 37th Lorne Cancer Conference 2025

Revealing Master Transcription Factor Networks Driving Neuroendocrine-like Reprogramming in Prostate Cancer (#284)

Tianjun Zhang 1 2 , Suzanne Maiolo 1 2 , Joanna Gillis 3 4 , Swati Irani 3 4 , Dulce L.M. García 1 2 , Lisa Butler 3 4 , Nora W. Liu 1 2 , Jose M. Polo 1 2
  1. Cancer Epigenetics Program, South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
  2. Adelaide Centre for Epigenetics, School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia
  3. Resistance Prevention Program, South Australian immunoGENomics Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
  4. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

  Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer with a poor prognosis and high resistance to therapy [1]. The median survival for patients with NEPC is seven months, and the five-year survival is less than 1% [2-3]. Clinical observations have noted the emergence of NEPC, often following androgen deprivation and hormonal therapies. Recent research analysing patient samples with single-cell transcriptomics suggests that NEPC may originate through a cell reprogramming process from prostate adenocarcinoma (PAC), the major subtype of prostate cancer [4-6]. However, the underlying mechanism of this NE-reprogramming process remains unclear, preventing further advances in NEPC treatment.

 

  To investigate the key transcriptional events mediating PAC reprogramming into NEPC, we first evaluated different models of NEPC progression using LNCaP cells. We used RNA sequencing to compare the transcriptional effects of different tissue culture strategies on NE progression. Our preliminary data suggest that LNCaP subpopulations can follow different reprogramming pathways driven by distinct transcription factor networks. We found cells inherently resistant to castration and highly proliferative, which exhibit a lower potential for NE differentiation, while cells more prone to NE reprogramming tend to be less proliferative. Additionally, we developed 3D organoid models from LNCaP cells and patient-derived primary tumours to capture the complexity of tumour architecture. By combining these models alongside publicly available clinical scRNA-seq data, we have identified master transcription factors involved in NE reprogramming.

 

  In summary, we are developing complex NE models to uncover the molecular events underpinning NEPC progression and to identify key transcriptional factor networks. Furthermore, by integrating in vitro models with clinical single-cell data, we aim to reveal novel mechanisms behind NEPC development and persistence. Ultimately, this work seeks to identify new therapeutic targets to reduce mortality and improve treatment outcomes for NEPC patients.



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  3. Sargos, P., et al., Characterization of prostate neuroendocrine cancers and therapeutic management: a literature review. Prostate Cancer Prostatic Dis, 2014. 17(3): p. 220-6.
  4. Dong, B., et al., Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer. Commun Biol, 2020. 3(1): p. 778.
  5. Beltran, H., et al., Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med, 2016. 22(3): p. 298-305.
  6. Wang, Z., et al., Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer. iScience, 2022. 25(7): p. 104576.