PO.MCB07.02 · 分子与细胞生物学

RUNX1T1作为治疗诱导性神经内分泌转分化的早期驱动因子

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 Authors & Affiliations

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

中文摘要

治疗诱导性神经内分泌前列腺癌（t-NEPC）是一种致死性的去势抵抗变异型，主要通过前列腺腺癌在雄激素剥夺治疗（ADT）和雄激素受体通路抑制剂（ARPI）后发生神经内分泌（NE）转分化而产生。尽管具有临床相关性，启动这一转变的早期分子事件仍不明确。我们利用首个且唯一捕捉腺癌向NEPC转分化的纵向患者来源异种移植（PDX）模型（LTL331/331R），对涵盖去势前、去势后/过渡阶段以及复发NEPC的七个关键阶段进行了单细胞RNA测序（scRNA-seq）。聚类分析鉴定出15个主要细胞群，并揭示了一个此前未被认识的中间过渡细胞状态，该状态富集上皮-间质转化（EMT）、干性、代谢活性以及HDAC相关调控特征，凸显了一个独特的谱系可塑性窗口。两个具有ASCL1/FOXA2互补表达模式的终末NEPC亚群反映了复发时的肿瘤内异质性。对过渡细胞群的转录分析鉴定出RUNX1T1为可塑性早期出现的核心调控因子。功能实验显示，RUNX1T1过表达显著加速AR通路抑制诱导的NE转分化，并在前列腺腺癌模型中赋予对ARPI治疗的抵抗。相反，RUNX1T1敲低可降低NE相关通路的表达、抑制NEPC细胞生长并诱导凋亡。这些发现确立RUNX1T1为NEPC发生和进展的必需因子。机制上，快速免疫沉淀与质谱联用（RIME）揭示RUNX1T1与多种抑制性表观遗传因子相互作用，包括含HDAC的复合物和异染色质相关基因。这些结果支持RUNX1T1在NEPC发生过程中介导转录沉默和调控网络重编程的作用。总之，本研究以单细胞分辨率描绘了t-NEPC的时间演化，鉴定出NE转分化过程中的一个中间过渡状态，并揭示了终末NEPC内部的异质性。将RUNX1T1鉴定为这一轨迹的早期且持续存在的驱动因子，使RUNX1T1及其相关抑制性复合物成为有前景的治疗干预候选靶点。

查看英文原文 English 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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