PO.MCB07.02 · 分子与细胞生物学

RUNX1T1 as an early driver in treatment-induced neuroendocrine transdifferentiation

编号 7249 展板 16 时间 4/22 09:00–12:00 区域 Section 20 主讲 Ace Mingchen Shi, PhD

分会场 Chromatin Architecture and Regulatory Landscapes

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作者与单位

Yuchao Ni¹, Mingchen Shi², Dong Lin², Yen-Yi Lin³, Hui Xue⁴, Xin Dong⁴, Liangliang Liu³, Funda Sar³, Rebecca Wu⁴, Tunc Morova³, Anne Hargert³, Robert Bell³, Xinyao Pang², Adam Classen², Yu Wang², Junru Chen⁵, Stephan Le Bihan³, Wei Dong⁶, Vickie Wang⁷, Ning Xu⁸, Nathan Lack³, Martin E. Gleave³, Christopher J. Ong⁹, Gang Wang¹⁰, Hao Zeng¹¹, Colin Collins³, Yuzhuo Wang²

¹Vancouver Prostate Centre; University of British Columbia; Urology Research Institute, The First Affiliated Hospital, Fujian Medical University, Vancouver, BC, Canada,²Vancouver Prostate Centre; BC Cancer; University of British Columbia, Vancouver, BC, Canada,³Vancouver Prostate Centre; University of British Columbia, Vancouver, BC, Canada,⁴Vancouver Prostate Centre; BC Cancer, Vancouver, BC, Canada,⁵Vancouver Prostate Centre; BC Cancer; University of British Columbia; Institute of Urology, West China Hospital Sichuan University, Vancouver, BC, Canada,⁶Vancouver Prostate Centre; University of British Columbia；Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Vancouver, BC, Canada,⁷University of British Columbia, Vancouver, BC, Canada,⁸Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China,⁹Surgery, Vancouver Prostate Centre; University of British Columbia, Vancouver, BC, Canada,¹⁰BC Cancer; University of British Columbia, Vancouver, BC, Canada,¹¹Institute of Urology, West China Hospital, Sichuan University, Chengdu, China

摘要 Abstract

Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal form of castration-resistant variant arising primarily through neuroendocrine (NE) transdifferentiation of prostate adenocarcinoma following androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPI). Despite its clinical relevance, the early molecular events initiating this transition remain poorly defined. Leveraging the first and only longitudinal patient-derived xenograft (PDX) model capturing adenocarcinoma-to-NEPC transdifferentiation (LTL331/331R), we performed single-cell RNA sequencing (scRNA-seq) across seven key stages spanning pre-castration, post-castration/ transitional phases, and relapsed NEPC.Clustering analysis identified 15 major cell populations and revealed a previously unrecognized intermediate transitional cell state enriched for epithelial-mesenchymal transition (EMT), stemness, metabolic activity, and HDAC-related regulatory signatures, highlighting a unique window of lineage plasticity. Two terminal NEPC subclusters with reciprocal ASCL1/FOXA2 expression patterns reflected intratumoral heterogeneity at relapse.Transcriptional interrogation of the transitional population identified RUNX1T1 as a central regulator emerging early during plasticity. Functional assays revealed that RUNX1T1 overexpression markedly accelerates AR pathway inhibition-induced NE transdifferentiation and confers resistance to ARPI therapy in prostate adenocarcinoma models. Conversely, RUNX1T1 knockdown reduces NE-related pathway expression, suppresses NEPC cell growth, and induces apoptosis. These findings position RUNX1T1 as an essential factor for both NEPC development and progression.Mechanistically, rapid immunoprecipitation and mass spectrometry (RIME) uncovered that RUNX1T1 interacts with multiple repressive epigenetic factors including HDAC-containing complexes and heterochromatin-related genes. These results support a role for RUNX1T1 in mediating transcriptional silencing and regulatory network reprogramming during NEPC development.In summary, this study delineates the temporal evolution of t-NEPC at single-cell resolution, identifies an intermediate transitional state during NE transdifferentiation, and reveals heterogeneity within terminal NEPC. The identification of RUNX1T1 as an early and persistent driver of this trajectory positions RUNX1T1 and its associated repressive complexes as promising candidates for therapeutic intervention.

利益披露 Disclosure

Y. Ni, None.. M. Shi, None.. D. Lin, None.. Y. Lin, None.. H. Xue, None.. X. Dong, None.. L. Liu, None.. F. Sar, None.. R. Wu, None.. T. Morova, None.. A. Hargert, None.. R. Bell, None.. X. Pang, None.. A. Classen, None.. Y. Wang, None.. J. Chen, None.. S. Le Bihan, None.. W. Dong, None.. V. Wang, None.. N. Xu, None.. N. Lack, None.. M. E. Gleave, None.. C. J. Ong, None.. G. Wang, None.. H. Zeng, None.. C. Collins, None.. Y. Wang, None.

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