Liu Liangliang, Rascón Itzel Astiazarán, Lin Dong, Ni Yuchao, Dong Xin, Xue Hui, Lin Yen-Yi, Haegert Anne, Sar Funda, Peacock James W, Tombe Tabitha, Dusek Christopher, Zoubeidi Amina, Gleave Martin E, Collins Colin, Bénard Francois, Wang Yuzhuo, Ong Christopher J
Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada.
BC Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Cell Genom. 2025 Aug 13;5(8):100916. doi: 10.1016/j.xgen.2025.100916. Epub 2025 Jun 10.
Phenotypic switching is an emerging driver of cancer treatment resistance, yet early signals regulating this process remain unclear. Here, using longitudinal single-cell RNA sequencing, we mapped differentiation trajectories in the LTL331 prostate adenocarcinoma patient-derived xenograft (PDX) model undergoing neuroendocrine prostate cancer (NEPC) transformation post castration. Our analyses identified a key differentiation node marked by epithelial-mesenchymal transition (EMT) and repressor element-1 silencing transcription factor (REST) downregulation driven by the CXCR4-LASP1-G9a-SNAIL axis. Mechanistically, CXCR4 activation promotes nuclear translocation of LASP1 that links G9a and SNAIL via SH3/proline-rich motif and LIM/SNAG domain interactions, enabling SNAIL-mediated REST repression via promoter E-box motifs. Inhibition of CXCR4 or G9a reversed LTL331R NEPC cells toward a luminal androgen receptor-active phenotype. CXCR4-targeted radioligands enabled both imaging and inhibition of NEPC tumors in vivo. These findings highlight the CXCR4-LASP1-G9a-SNAIL axis as a key regulator of epigenetic and transcriptional reprogramming in NEPC transdifferentiation and support its therapeutic targeting in aggressive NEPC.
表型转换是癌症治疗耐药性的一个新出现的驱动因素，但调节这一过程的早期信号仍不清楚。在这里，我们使用纵向单细胞RNA测序技术，在去势后发生神经内分泌前列腺癌（NEPC）转化的LTL331前列腺腺癌患者来源异种移植（PDX）模型中绘制了分化轨迹。我们的分析确定了一个关键的分化节点，其特征是由CXCR4-LASP1-G9a-SNAIL轴驱动的上皮-间质转化（EMT）和阻遏元件1沉默转录因子（REST）下调。从机制上讲，CXCR4激活促进LASP1的核转位，LASP1通过SH3/富含脯氨酸基序和LIM/SNAG结构域相互作用将G9a和SNAIL联系起来，从而通过启动子E-box基序实现SNAIL介导的REST抑制。抑制CXCR4或G9a可使LTL331R NEPC细胞向腔面雄激素受体活性表型逆转。靶向CXCR4的放射性配体能够在体内对NEPC肿瘤进行成像和抑制。这些发现突出了CXCR4-LASP1-G9a-SNAIL轴是NEPC转分化过程中表观遗传和转录重编程的关键调节因子，并支持将其作为侵袭性NEPC的治疗靶点。
