PlexinD1 is a Driver and a Therapeutic Target in Advanced Prostate Cancer

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.

与雄激素受体信号通路抑制剂（androgen receptor signaling inhibitor, ARSI）耐药及转移相关的侵袭性前列腺癌（prostate cancer, PCa）亚型，目前的研究认知仍较为有限。本研究鉴定出轴突导向信号素受体PlexinD1是转移性去势抵抗性前列腺癌（castration-resistant prostate cancer, CRPC）中癌症侵袭性的关键驱动因子。人类前列腺癌组织中PlexinD1的高表达与不良临床结局显著相关。PlexinD1可在体外与体内维持去势抵抗性前列腺癌的侵袭性行为，并赋予癌细胞干细胞特性与细胞可塑性，以促进多谱系分化，包括介导ARSI耐药的神经内分泌样表型。从机制层面来看，在ARSI处理条件下，雄激素受体（androgen receptor, AR）对PlexinD1的转录抑制被解除，从而上调PlexinD1的表达；随后PlexinD1通过直接相互作用反式激活ErbB3与cMet，进而触发ERK/AKT信号通路，诱导非经典的Gli1介导型Hedgehog信号通路活化，最终促进前列腺癌细胞的增殖与可塑性。采用蛋白抑制剂D1SP阻断PlexinD1，可在多种临床前模型中抑制去势抵抗性前列腺癌的生长。综上，本研究明确了PlexinD1在前列腺癌进展中的核心作用，并为晚期前列腺癌提供了一种潜在的PlexinD1靶向治疗策略。