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: 10612347
• 负责人: CHARLES L. SAWYERS
• 金额: $ 49.32万
• 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/10612347
• 关键词: Abate; Acceleration; 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 Cells; Epithelium; 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; Invaded; Investigation; Laboratory Finding; Large-Scale Sequencing; 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; Stromal Cells; T-Lymphocyte; Technology; Tissue Recombination; Tissue Sample; Translating; Tumor Promotion; Tumor-infiltrating immune cells; Uncertainty; WNT Signaling Pathway; Work; advanced disease; advanced prostate cancer; antagonist; cytokine; data management; drug efficacy; experience; hormone therapy; human tissue; immune cell infiltrate; 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; synergism; 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.

项目摘要/摘要 大规模测序工作已全面定义了局部和 转移性前列腺癌，对疾病启动驱动因素和进展的驱动力有了改进的了解 以及对抗雄激素受体（AR）途径抗性机制的更深入的了解。一个限制 在这种“肿瘤细胞”基因组方法中，相对缺乏对肿瘤微环境的洞察力 （TME）发挥作用。但是，单细胞测序技术的最新进展为 全面地以前所未有的精度检查肿瘤/微环境相互作用。我们的小组有 接受这种方法：最初是在正常前列腺中表征上皮/基质相互作用，现在 描绘一般工程的小鼠模型（GEMM）中的肿瘤细胞/微环境相互作用 前列腺癌。这些研究揭示了罢工的复杂程度。我们不仅以前定义了 正常前列腺中腔上皮细胞和基质细胞的未知亚群，但我们也有 展示了这些人群在进展为侵入性疾病期间的变化/演变以及对AR的响应 途径抑制（即cast割）。此外，我们的初步数据显示了肿瘤浸润的部署 免疫细胞延迟疾病的进展消除了这些TME变化是次要的任何疑问 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）发挥了A 在疾病进展中的关键作用。我们将通过三个协同特定的目的来探讨这一假设： （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侵袭； （iii） 确定/是否/如何受到AR途径抑制的反应受抑制的影响 在周围的TME细胞中AR。我们在GEMM，组织重组测定方面有丰富的经验 和器官文化将用于解决这些问题。我们也有很强的记录 将实验室发现转化为诊所，这将确保我们发现的人类相关性。最后，这个 项目与该计划项目的所有其他组件高度集成：通过协作互动 在分析对神经内分泌疾病的过渡时，与沉的实验室一起进行了Abate-Shen实验室 骨转移中的Wnt途径信号传导，核心A用于分析人类组织样品和核心B 用于统计支持和数据管理。