LC3b高表达管腔干细胞在前列腺再生和AR非依赖型肿瘤发生与发展的作用研究

第二代雄激素剥夺法（ADT）为去势抵抗前列腺癌（CRPC）的主要治疗方案。遗憾的是，ADT治疗后的CRPC最终都发展成雄激素受体（AR）非依赖肿瘤（AIPC）。然而，AIPC起源细胞的身份及分子特征尚不明确。我们前期研究发现，AR非依赖前列腺上皮细胞具备干细胞特性，而部分的管腔细胞呈LC3b高表达的状况；同时，LC3b高表达前列腺管腔细胞具备更高的类器官形成率，预示了它们的干细胞潜能；此外，CRPC和AIPC肿瘤模型及病患的肿瘤标本都呈现LC3b高表达的情况，提示LC3b有可能在AIPC发生与发展中扮演着重要的角色。在本项目中，我们将鉴定LC3b高表达AR非依赖前列腺管腔细胞的干细胞潜能及分子特征，同时评估其作为AIPC起源细胞的能力；同时，探究LC3b高表达癌细胞在第二代ADT抵抗进程中的作用及临床意义。综上所述，此研究将为克服第二代ADT耐药难题上提供全新治疗策略和靶标。

Second-generation androgen deprivation therapy (ADT) remains as the major therapeutic option for castration-resistant prostate cancer (CRPC). Unluckily, almost all CRPC patients receiving second-generation ADT will eventually progress into androgen receptor (AR)-independent prostate cancer (AIPC). However, the cell of origin for AIPC as well as the molecular properties that contribute to the formation of AIPC remain unclear. In preliminary studies, we have demonstrated that AR-independent prostate epithelial cells possess progenitor properties, whereas part of the luminal cells within the AR-independent prostate epithelium demonstrates high expression of LC3b. Our subsequent analysis has revealed that high LC3b-expressing prostate luminal cells are more capable to generate organoids when compared to the LC3b negative counterpart, indicating that this population has great progenitor potential. Moreover, we have also discovered high expression of LC3b in CRPC and AIPC tumor models and patient tumor specimens, suggesting that high LC3b-expressing cancer cells may have a crucial role in AIPC initiation and progression. In the proposed research works, we will determine the progenitor properties and molecular characteristic of high LC3b-expressing AR-independent prostate luminal cells and their ability to serve as the cell of origin for AIPC. In addition, we will also investigate the functional role of high LC3b-expressing cancer cells in second-generation ADT failure and their clinical prognostic significance. Consequently, targeting the high LC3b-expressing AR-independent prostate progenitors and cancer cells as well as their molecular properties may serve as novel therapeutic strategies to overcome second-generation ADT resistance.