Project 1: Investigation of immune and stromal factors that promote prostate adenocarcinoma progression and castration response

项目摘要/摘要 大规模的测序工作已经全面定义了本地化的和 转移性前列腺癌，对疾病发生和发展的驱动因素有了更好的理解 以及对雄激素受体(AR)途径抑制的抵抗机制的更深入的了解。一个限制 这种“以肿瘤细胞为中心”的基因组方法是相对缺乏对肿瘤微环境 (TME)发挥了作用。然而，单细胞测序技术的最新进展为 以前所未有的精确度全面检查肿瘤/微环境的相互作用。我们的团队已经 采用了这种方法：最初是为了描述正常前列腺中上皮/间质的相互作用，现在是 在基因工程小鼠模型(GEMM)中描述肿瘤细胞/微环境的相互作用 前列腺癌。这些研究揭示了惊人的复杂性。我们不仅在前面定义了 正常前列腺中未知的管腔上皮和基质细胞亚群，但我们也有 显示了这些种群在发展为侵袭性疾病以及对AR的响应过程中如何变化/进化 途径抑制(即去势)。此外，我们的初步数据显示，肿瘤浸润性疾病的耗竭 免疫细胞延缓疾病进展消除了任何疑问，即这些TME变化是继发性的 现象。 基于这些发现，我们假设前列腺TME(免疫细胞和基质细胞)在 在疾病发展中起着至关重要的作用。我们将通过三个协同的具体目标来探索这一假设： (I)阐明肿瘤浸润性免疫细胞促进肿瘤进展的机制；。(Ii)阐明 前列腺间质中Wnt通路信号的变化如何促进肿瘤上皮细胞的侵袭；以及 确定抑制AR通路是否/如何影响前列腺癌对AR通路抑制的反应 在周围的TME细胞中有AR。我们在GEMM、组织重组分析方面拥有丰富的经验 和器官培养，将被用来解决这些问题。我们也有很好的记录， 将实验室发现转化为临床，这将确保我们的发现与人类相关。最后，这一点 项目与该计划项目的所有其他组件高度集成：通过协作交互 与沈氏实验室合作分析向神经内分泌疾病的过渡，与阿巴特-沈实验室合作研究 骨转移中的WNT通路信号，核心A用于分析人体组织样本，核心B 用于统计支持和数据管理。

Project Summary/Abstract Large scale sequencing efforts have comprehensively defined the genomic landscape of localized and metastatic prostate cancer, yielding an improved understanding of drivers of disease initiation and progression and greater insight into mechanisms of resistance to androgen receptor (AR) pathway inhibition. One limitation of this “tumor cell focused” genomic approach is a relative lack of insight into how the tumor microenvironment (TME) plays a role. However, recent advances in single cell sequencing technologies have opened the door to comprehensively examine tumor/microenvironment interactions with unprecedented precision. Our group has embraced this approach: initially to characterize epithelial/stromal interactions in the normal prostate, and now to delineate tumor cell/microenvironment interactions in genetically engineered mouse models (GEMMs) of prostate cancer. These studies reveal a striking level of complexity. We have not only defined previously unknown subpopulations of luminal epithelial and stromal cells in the normal prostate gland, but also we have shown how these populations change/evolve during progression to invasive disease and in response to AR pathway inhibition (i.e. castration). In addition, our preliminary data showing that depletion of tumor-infiltrating immune cells delays disease progression eliminates any doubt that these TME changes are secondary phenomena. Based on these findings, we hypothesize that the prostate TME (immune cells and stromal cells) plays a crucial role in disease progression. We will explore this hypothesis through three synergistic specific aims that: (i) address the mechanism by which tumor infiltrating immune cells enhance tumor progression; (ii) elucidate how changes in Wnt pathway signaling in prostate stroma promote invasion by tumor epithelium; and (iii) determine whether/how the response of prostate tumors to AR pathway inhibition is influenced by inhibition of AR in the surrounding TME cells. We have extensive experience with the GEMMs, tissue recombination assays and organoid culture that will be used to address these questions. We also have a strong track record of translating laboratory findings to the clinic, which will ensure the human relevance of our findings. Finally, this project is highly integrated with all other components of this program project: through collaborative interactions with the Shen lab in analyzing the transition to neuroendocrine disease, with the Abate-Shen lab in studies of Wnt pathway signaling in bone metastasis, with Core A for analysis of human tissue samples and with Core B for statistical support and data management.