Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors. Mice bearing patient-derived prostate cancer xenografts were surgically castrated. Tissues for microarray profiling and analyses were harvested at pre-castration and post-castration 12 week timepoints, respectively.

研究目的：治疗诱导的肿瘤休眠是癌症进展中的一类特殊状态，此时体内存在残留病灶但无临床症状。休眠癌细胞具有治疗抗性，是癌症复发与转移的核心诱因。接受雄激素剥夺疗法（androgen-deprivation therapy, ADT）治疗的前列腺癌（prostate cancer, PCa）常可进入休眠状态。但由于临床休眠态前列腺癌细胞获取难度极大，且缺乏合适的代表性研究模型，ADT诱导的前列腺癌休眠机制目前仍未得到充分阐明。因此，本研究旨在开发可用于研究ADT诱导的前列腺癌休眠的临床相关模型。
实验设计：我们对携带激素初治或激素敏感型前列腺癌患者来源异种移植瘤（patient-derived xenografts, PDXs）的小鼠实施去势手术，以此构建休眠态前列腺癌模型。对肿瘤休眠状态与复发情况进行全程监测与评估。分别采集去势前与去势后（休眠态）的配对PDX组织，开展形态学与转录组特征分析。
研究结果：本研究成功构建了11株ADT诱导的休眠态前列腺癌模型，该系列模型可精准模拟接受ADT治疗的前列腺癌患者的临床病程。我们鉴定出两种ADT诱导的休眠亚型，二者在形态学特征、基因表达谱及复发率方面均存在显著差异。我们发现去势前的PDX组织存在固有转录组差异，这些差异可预先决定肿瘤对ADT的休眠应答倾向。进一步，我们开发了基于休眠亚型的易感基因特征，该特征与激素初治前列腺癌的ADT应答效果、以及接受ADT或雄激素受体通路抑制剂治疗的去势抵抗性前列腺癌患者的临床预后均显著相关。具体实验流程为：对携带患者来源前列腺癌异种移植瘤的小鼠实施外科去势手术，分别于去势前与去势后12周采集组织，用于基因芯片谱分析及相关研究。