前列腺癌异质性转化PDX模型的建立及其在骨转移机制研究中的应用

异质性转化是导致前列腺癌（Pca）难以治愈的主要原因，相关机制不明确。为此创建的PDX模型虽较好地保持了原发瘤的特征，但无法反映其临床常见的NEPC转化和AVPC引起的骨转移。已证实AR信号是诱导Pca异质性转化的重要因素；实验发现Pca瘤组织中JARIDID和MAOA的表达变化可促进骨转移，且均与AR水平密切相关。据此，我们提出科学假说：AR信号可诱导前列腺癌PDX模型发生NEPC和AVPC转化，进而调控JARID1D和MAOA的表达促进骨转移，形成完整反映Pca临床特征的PDX模型。本研究计划探索AR靶向抑制剂诱导前列腺癌PDX模型发生转化的可行性；运用Array，WB和IHC等技术，分析AR信号调控JARID1D和MAOA表达变化诱导骨转移发生的机制；尝试将上述靶基因用于筛选骨转移模型，完整再现Pca临床异质性，从而为研究Pca转化机制，特别是骨转移的发生提供理想的动物模型。

Heterogeneous progress is the main reason leading prostate cancer (Pca) to cure difficultly, and the related mechanism remains poorly understood. Thus, more Pca patient derived xenograft (PDX) models have been established for this study. Although these models well maintain the heterogeneity of the original tumor, they do not reflect the clinical progress feature of castration resistance prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC), especially lack of bone metastasis characteristic caused by aggressive variant prostate cancer (AVPC). It has been proved that androgen receptor (AR) signaling is critical cause inducing prostate cancer clinical heterogeneous progress. Our previous studies also demonstrated that the expression changes of demethylase JARID1D and monoamine oxidase A (MAOA) in Pca tumor tissue promote the occurrence of bone metastasis. Therefore, we speculate that AR signal molecules can induce Pca PDX model heterogeneous progress (including NEPC and AVPC), further promote the occurrence of bone metastasis by regulating the expression of JARID1D and MAOA, thus to form PDX models that completely reflect the clinical progress of prostate cancer. This project is designed to explore the feasibility of inducing NEPC and AVPC progress in the prostate cancer PDX model by AR target inhibitor therapy. We will analyze how AR signal molecules regulate the expression of JARID1D and MAOA to induce bone metastasis using Array, Western-blot and IHC technology. Those two target genes are further applied to screen bone metastasis models. Thus, the PDX model that faithfully recapitulates the clinical heterogeneity of prostate cancer has been established. This study will provide the ideal animal models for studying the clinical progress mechanism of prostate cancer, especially for understanding bone metastasis mechanism.