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

项目总结/摘要 大规模的测序工作已经全面地定义了局部和局部的基因组景观。 转移性前列腺癌，提高了对疾病发生和进展驱动因素的理解 以及对雄激素受体（AR）通路抑制的抗性机制的更深入了解。一个限制 这种“以肿瘤细胞为中心”的基因组方法的缺点是相对缺乏对肿瘤微环境如何 (TME)扮演了一个角色。然而，单细胞测序技术的最新进展已经打开了 以前所未有的精度全面检查肿瘤/微环境相互作用。我们集团 采用这种方法：最初是为了表征正常前列腺中上皮/基质的相互作用，现在 描述肿瘤细胞/微环境在遗传工程小鼠模型（GEMM）中的相互作用， 前列腺癌这些研究揭示了惊人的复杂性。我们不仅定义了 在正常前列腺中，我们发现了未知的腔上皮细胞和基质细胞亚群，而且我们还发现了 显示了这些人群在进展为侵袭性疾病和对AR的反应中如何变化/演变 途径抑制（即去势）。此外，我们的初步数据显示， 免疫细胞延迟疾病进展消除了对这些TME变化是继发性的任何疑问 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）在前列腺中起着重要作用。 在疾病进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讨这一假设，即： (i)解决肿瘤浸润免疫细胞增强肿瘤进展的机制;（ii）阐明 前列腺基质中Wnt途径信号传导的变化如何促进肿瘤上皮的侵袭;以及（iii） 确定前列腺肿瘤对AR途径抑制的反应是否/如何受到以下抑制的影响： 周围TME细胞中的AR。我们在GEMM、组织重组检测方面拥有丰富的经验 和类器官培养来解决这些问题。我们也有一个强大的跟踪记录， 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 项目与本计划项目的所有其他组成部分高度集成：通过协作互动 与Shen实验室合作分析向神经内分泌疾病的转变，与Abate-Shen实验室合作研究 骨转移中的Wnt途径信号传导，核心A用于分析人组织样品，核心B用于分析人组织样品 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.