Longitudinal single-cell analysis reveals RUNX1T1 as an early driver in treatment-induced neuroendocrine transdifferentiation

  1. Yuchao Ni
  2. Dong Lin
  3. Mingchen Shi
  4. Yen-Yi Lin
  5. Hui Xue
  6. Xin Dong
  7. Liangliang Liu
  8. Funda Sar
  9. Rebecca Wu
  10. Tunc Morova
  11. Anne Haegert
  12. Robert Bell
  13. Xinyao Pang
  14. Adam Classen
  15. Yu Wang
  16. Junru Chen
  17. Stanislav Volik
  18. Stéphane Le Bihan
  19. Nathan Lack
  20. Christopher Ong
  21. Gang Wang
  22. Hao Zeng
  23. Colin Collins
  24. Yuzhuo Wang
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Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal, castration-resistant subtype of prostate cancer. While t-NEPC typically arises from adenocarcinoma through neuroendocrine transdifferentiation after androgen pathway inhibition, the temporal dynamics and molecular drivers of this process remain poorly understood. Here, utilizing the first-in-field patient-derived xenograft (PDX) model of adenocarcinoma-to-NEPC transdifferentiation (LTL331/331R), we performed longitudinal single-cell transcriptomic sequencing (scRNA-seq) across seven timepoints spanning pre-castration to relapsed NEPC. Our analysis demonstrated 15 distinct cell clusters, including twelve adenocarcinoma clusters and two NEPC clusters (ASCL1high/FOXA2lowandASCL1low/FOXA2highclusters). Notably, we revealed a newly-discovered, early intermediate transitional cell state during t-NEPC development distinguished by epithelial-mesenchymal transition (EMT), stem cell-related, metabolically active, and HDAC-associated regulatory signatures. Analysis of this intermediate transitional cluster led to the identification ofRUNX1T1as a pivotal transcriptional regulator of NEPC transdifferentiation. Functionally,RUNX1T1overexpression promoted AR pathway inhibition (ARPI) -induced NE transdifferentiation and increased resistance to ARPI treatment in prostate adenocarcinoma.RUNX1T1knockdown reverses the NE transdifferentiation, inhibits NEPC cell proliferation and induces apoptosis, and cell cycle arrest. In summary, this study identifies a critical intermediate transitional cell state during t-NEPC development and reveals the heterogeneity of terminal NEPC, offering new insights into NEPC biology and emphasizing the importance of early intervention. Moreover, the discovery ofRUNX1T1as a key early driver active in both the initial and terminal phases of NEPC progression presents promising opportunities for therapeutic intervention.

Highlights

  • Longitudinal single-cell RNA sequencing of treatment-induced adeno-to-NE transdifferentiation model revealed an intermediate transitional cell state in NEPC development and progression.

  • The sequential emergence ofASCL1high/FOXA2lowandASCL1low/FOXA2highNEPC subclusters indicates a temporal evolution of NEPC and highlights their role in contributing to NEPC heterogeneity.

  • RUNX1T1, a transcriptional regulator showing increased expression in both intermediate cell state and NEPCs, is identified as an early driver of NEPC development.

  • RUNX1T1 plays important functional roles in promoting adeno-to-NE transdifferentiation in early phase of NEPC development and maintaining NE phenotype and aggressiveness in terminal NEPC.

  • Targeting RUNX1T1 or its complex could offer new therapeutic strategies for NEPC management.

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