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

项目1：促进前列腺腺癌进展和去势反应的免疫和基质因子的研究

• 批准号: 10333943
• 负责人: CHARLES L. SAWYERS
• 金额: $ 69.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333943
• 关键词: Abate; Address; Affect; Alleles; Androgen Antagonists; Androgen Receptor; Antiandrogen Therapy; Antibodies; Area; Biological Assay; Biology; Blocking Antibodies; Bone Marrow; CSF1R gene; Castration; Cells; Clinic; Clinical; Clinical Research; Collaborations; Combined Modality Therapy; Data; Data Set; Disease; Disease Progression; Drug Targeting; Ensure; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; FDA approved; Fibroblasts; Fluorescence; Gene Expression Profile; Gene Expression Profiling; Genetically Engineered Mouse; Genomic approach; Genomics; Hormonal; Hormone use; Human; Immune; Immune checkpoint inhibitor; Infiltration; Inflammatory; Investigation; Laboratory Finding; Large-Scale Sequencing; Lead; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Mesenchymal; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neurosecretory Systems; Organoids; Outcome; Pathogenesis; Pathway interactions; Play; Population; Prostate; Prostate Adenocarcinoma; Prostatic Neoplasms; Proteins; Publishing; Receptor Inhibition; Receptor Signaling; Reporter; Role; Sampling; Signal Transduction; Sorting - Cell Movement; Stromal Cells; T-Lymphocyte; Technology; Tissue Recombination; Tissue Sample; Translating; Tumor Cell Invasion; Tumor-infiltrating immune cells; Uncertainty; WNT Signaling Pathway; Work; advanced disease; advanced prostate cancer; antagonist; base; cytokine; data management; drug efficacy; experience; hormone therapy; human tissue; improved; in vivo; insight; neoplastic cell; neuroendocrine differentiation; novel; programs; prostate cancer model; prostate cancer progression; recombinase; reconstitution; resistance mechanism; response; single cell sequencing; single cell technology; single-cell RNA sequencing; tissue resource; tool; treatment effect; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

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.

项目概要/摘要 大规模测序工作已经全面定义了局部和局部的基因组景观 转移性前列腺癌，更好地了解疾病发生和进展的驱动因素 以及对雄激素受体（AR）通路抑制的抵抗机制有更深入的了解。一项限制 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发挥作用的了解。 （TME）发挥了作用。然而，单细胞测序技术的最新进展为 以前所未有的精度全面检查肿瘤/微环境相互作用。我们组有 采用了这种方法：最初是为了表征正常前列腺中的上皮/基质相互作用，现在 描述基因工程小鼠模型（GEMM）中肿瘤细胞/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。我们之前不仅定义了 正常前列腺中的管腔上皮细胞和基质细胞的未知亚群，但我们也有 显示了这些人群在侵袭性疾病进展过程中以及对 AR 的反应如何变化/进化 途径抑制（即去势）。此外，我们的初步数据表明，肿瘤浸润的减少 免疫细胞延缓疾病进展，消除了人们对这些 TME 变化是次要的怀疑 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）发挥着重要作用 在疾病进展中发挥重要作用。我们将通过三个协同的具体目标来探索这一假设： (i) 解决肿瘤浸润免疫细胞促进肿瘤进展的机制； (二) 阐明 前列腺基质中 Wnt 通路信号的变化如何促进肿瘤上皮的侵袭； (三) 确定前列腺肿瘤对 AR 通路抑制的反应是否/如何受到抑制的影响 AR 位于周围 TME 细胞中。我们在 GEMM、组织重组检测方面拥有丰富的经验 和用于解决这些问题的类器官培养。我们还拥有良好的记录 将实验室研究结果转化为临床，这将确保我们的研究结果与人类相关。最后，这个 项目与该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 通路信号传导，使用 Core A 分析人体组织样本，使用 Core B 用于统计支持和数据管理。