Wei Jing, Wang Jing, Guan Wen, Li Jingjing, Pu Tianjie, Corey Eva, Lin Tzu-Ping, Gao Allen C, Wu Boyang Jason
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
EMBO Mol Med. 2025 Feb;17(2):336-364. doi: 10.1038/s44321-024-00186-z. Epub 2025 Jan 2.
Aggressive prostate cancer (PCa) variants associated with androgen receptor signaling inhibitor (ARSI) resistance and metastasis remain poorly understood. Here, we identify the axon guidance semaphorin receptor PlexinD1 as a crucial driver of cancer aggressiveness in metastatic castration-resistant prostate cancer (CRPC). High PlexinD1 expression in human PCa is correlated with adverse clinical outcomes. PlexinD1 critically maintains CRPC aggressive behaviors in vitro and in vivo, and confers stemness and cellular plasticity to promote multilineage differentiation including a neuroendocrine-like phenotype for ARSI resistance. Mechanistically, PlexinD1 is upregulated upon relief of AR-mediated transcriptional repression of PlexinD1 under ARSI treatment, and subsdquently transactivates ErbB3 and cMet via direct interaction, which triggers the ERK/AKT pathways to induce noncanonical Gli1-dictated Hedgehog signaling, facilitating the growth and plasticity of PCa cells. Blockade of PlexinD1 by the protein inhibitor D1SP restricted CRPC growth in multiple preclinical models. Collectively, these findings characterize PlexinD1's contribution to PCa progression and offer a potential PlexinD1-targeted therapy for advanced PCa.
与雄激素受体信号抑制剂（ARSI）耐药性和转移相关的侵袭性前列腺癌（PCa）变体仍未得到充分了解。在此，我们确定轴突导向信号素受体PlexinD1是转移性去势抵抗性前列腺癌（CRPC）中癌症侵袭性的关键驱动因素。人PCa中PlexinD1的高表达与不良临床结果相关。PlexinD1在体外和体内都对CRPC的侵袭性行为至关重要，并赋予干性和细胞可塑性以促进多谱系分化，包括产生对ARSI耐药的神经内分泌样表型。机制上，在ARSI治疗下，AR介导的对PlexinD1的转录抑制解除后，PlexinD1被上调，随后通过直接相互作用反式激活ErbB3和cMet，触发ERK/AKT途径以诱导非经典Gli1主导的Hedgehog信号传导，促进PCa细胞的生长和可塑性。在多个临床前模型中，蛋白质抑制剂D1SP对PlexinD1的阻断限制了CRPC的生长。总的来说，这些发现描述了PlexinD1对PCa进展的作用，并为晚期PCa提供了一种潜在的以PlexinD1为靶点的治疗方法。
