第二代雄激素剥夺法（ADT）是去势抵抗型前列腺癌（CRPC）的主要治疗方法。不幸的是，几乎所有CRPC在ADT治疗后，最终发展成雄激素受体（AR）非依赖性疾病。部分CRPC通过神经内分泌分化（NED），进展成神经内分泌型前列腺癌（NEPC）。然而，NEPC起源细胞的身份及分子特征亟待深入研究。我们前期研究发现，前列腺管腔祖细胞，CARNs，在AR缺失后表达CRPC-NED相关的基因，并在致癌转化后形成局灶性NED肿瘤，这预示着CARNs作为NEPC起源细胞的潜能。在本项目中，我们将探究CARNs在AR缺失后作为NEPC起源细胞的能力；评估IL-8在维持AR缺失CARNs所表达的NED相关基因的作用及其作为NEPC起源细胞的能力；和探索从AR缺失CARNs筛选出的候选基因的NED驱动能力及其对第二代ADT治疗的预后意义。综上所述，本研究将为克服第二代ADT耐药问题提供全新治疗方案和靶标。

Second-generation androgen deprivation therapy (ADT), which targets intratumoral androgen biosynthesis or androgen receptor (AR) pathway, remains as the major treatment for castration-resistant prostate cancer (CRPC). Unluckily, one-third of CRPC patients demonstrate primary resistance to second-generation ADT, whereas the remaining patients eventually progress on an AR-independent disease after the treatment. Notably, certain CRPCs undergo neuroendocrine differentiation (NED) upon ADT, leading to the formation of neuroendocrine prostate cancer (NEPC) that is extremely lethal to the patients. However, the cell of origin as well as the molecular properties that enable NEPC formation remain unclear. In preliminary studies, we have demonstrated that 1) an AR-independent prostate luminal progenitor population called CARNs selectively express CRPC-NED-related genes upon AR deletion; 2) Pten deletion and mutated Kras activation in AR-deleted CARNs causes the formation of CRPC with focal NED; 3) IL-8 is the most differentially expressed upregulated gene in AR-deleted CARNs signature; 4) the identification of 34 novel genes from the AR-deleted CARNs signature that show gene amplification in >40% CRPC-NED specimen in a published patient cohort; and 5) the optimization of tissue recombination and organoid assays for cell of origin experiment and functional analyses of various candidate genes. Based on these preliminary results, we hypothesize that CARNs represent a cell of origin for NEPC upon loss of AR and oncogenic transformation with key drivers for NED, and that genetic alterations in AR-deleted CARNs predisposes them to generate NEPC upon treatment with ADT. In the proposed studies, we will use state-of-art genetically engineered mouse model, newly developed adherent lines from prostate luminal progenitors, novel tissue recombination and organoid assays to investigate 1) the ability of prostate luminal progenitors, CARNs to serve as the cell of origin for NEPCs upon loss of AR; 2) the role of IL-8 in prostate luminal progenitors-induced NED-related gene expression and NEPCs initiation upon loss of AR; and 3) the NED-driving ability and prognostic significance of novel differential expressed genes in AR-deleted prostate luminal progenitors in CRPC. Taken together, elucidation of the role of prostate luminal progenitors to serve as the cellular origin for NEPC upon loss of AR as well as their intrinsic molecular characteristics that enable NED should provide novel and timely insights into the development of NEPCs. Consequently, targeting the intrinsic AR-independent prostate luminal progenitor population and their molecular properties may serve as novel treatment strategies to overcome resistance to second-generation ADT.