Project 2: Investigating cell intrinsic and extrinsic drivers of prostate cancer bone metastasis

项目2：研究前列腺癌骨转移的细胞内在和外在驱动因素

• 批准号: 10612353
• 负责人: Cory Abate-Shen
• 金额: $ 47.35万
• 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/10612353
• 关键词: 3-Dimensional; Address; Affect; Allografting; Androgens; Biological; Biological Assay; Bromodomain; CRISPR screen; Cancer Etiology; Cells; Cellular Structures; Cessation of life; Coculture Techniques; Collaborations; Complement; Data; EP300 gene; Early Diagnosis; Evolution; Foundations; Genetic Complementation Test; Genetically Engineered Mouse; Habitats; Human; Immune; Immunologic Deficiency Syndromes; In Vitro; Investigation; LoxP-flanked allele; Malignant neoplasm of prostate; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Population; Primary Neoplasm; Process; Proteins; Regulation; Research; Role; Signal Transduction; Site; Specific qualifier value; Specificity; Tropism; Tumor-associated macrophages; Validation; Xenograft Model; Xenograft procedure; bone; candidate identification; candidate validation; cofactor; data management; deprivation; genome-wide; improved outcome; in vivo; in vivo Model; insight; member; men; mortality; mouse model; neoplastic cell; neuroendocrine differentiation; novel; organ on a chip; prostate cancer metastasis; prostate carcinogenesis; single cell sequencing; transcription factor; tumor microenvironment; tumor progression

Project Summary/Abstract The objective of our research is to elucidate tumor cell intrinsic and extrinsic mechanisms that give rise to bone metastasis and specify bone tropism. The foundation for our studies is the NPKYPF mouse model, which develops highly penetrant bone metastasis that is well-conserved with bone metastasis in human prostate cancer. Analyses of these mice enable investigations of the evolution of bone metastases during cancer progression in the native microenvironment in androgen-intact and androgen-deprived contexts. We have found that co-activation of MYC and RAS signaling is essential for bone metastasis, and that MYC activation is particularly relevant in contexts of androgen deprivation. Our preliminary studies have identified ATAD2 as a MYC-co-factor that is expressed in bone metastasis, particularly in contexts of androgen deprivation, and necessary for bone metastasis. In a complementary genome-wide in vivo CRISPR screening based on human prostate cancer xenografts, we identified CITED2, another MYC co-factor, as a cell-intrinsic driver of bone metastasis that it is sufficient to promote bone metastasis in vivo. Furthermore, single cell sequencing of primary tumors and bone metastases from NPKYPF mice has led to the identification master regulators (MRs) that are candidate cell intrinsic drivers of bone metastasis, while analyses of the non-tumor components have shown that primary tumors from metastatic NPKYPF mice are deficient for most immune cell populations, but highly enriched for tumor associated macrophages. Thus, we will investigate the hypothesis that bone metastasis represents the culmination of cell intrinsic drivers from the metastatic cells and tumor cell extrinsic factors in microenvironment of the metastatic bone. In Aim 1, we will investigate the hypothesis that CITED2 collaborates with MYC to promote bone specificity. In parallel, we will investigate candidate master regulators (MRs) associated with RAS pathway activation to elucidate their potential roles in bone metastasis. In Aim 2, we will investigate the hypothesis that ATAD2 is a co-factor for MYC in contexts of androgen deprivation, and elucidate the relationship of androgen status for the evolution and underlying mechanisms of bone metastasis. In Aim 3, we will investigate cell extrinsic mechanisms in the microenvironment of the primary tumor and metastatic bone, to identify relevant cell populations associated with metastasis, to evaluate their functional role for bone metastasis, and to identify cell extrinsic drivers of bone metastasis. Integration: Our studies are highly complementary to investigations of the tumor microenvironment for neuroendocrine differentiation (Project 3) and tumor progression (Project 1). Validation of candidate regulators for human bone metastasis will require Core A. Further, our systematic analysis of bone metastasis at the single cell level, complement efforts in Projects 1 and 3, while our ability to mutually benefit from these data will be enabled by the data management component of Core B.

项目概要/摘要 我们研究的目的是阐明肿瘤细胞产生的内在和外在机制 骨转移并指定骨向性。我们研究的基础是 NPKYPF 小鼠模型，该模型 形成高度渗透性骨转移，该骨转移与人类前列腺中的骨转移保存完好 癌症。对这些小鼠的分析可以研究癌症期间骨转移的演变 在雄激素完整和雄激素剥夺环境中的天然微环境中的进展。我们发现 MYC 和 RAS 信号传导的共同激活对于骨转移至关重要，并且 MYC 激活是 在雄激素剥夺的情况下尤其相关。我们的初步研究已确定 ATAD2 是 MYC辅助因子在骨转移中表达，特别是在雄激素剥夺的情况下，以及 骨转移所必需的。在基于人类的互补全基因组体内 CRISPR 筛选中 在前列腺癌异种移植物中，我们发现 CITED2（另一种 MYC 辅助因子）是骨的细胞内在驱动因素 足以促进体内骨转移。此外，原代细胞的单细胞测序 NPKYPF 小鼠的肿瘤和骨转移导致鉴定主调节因子 (MR) 骨转移的候选细胞内在驱动因素，而对非肿瘤成分的分析表明， 来自转移性 NPKYPF 小鼠的原发性肿瘤缺乏大多数免疫细胞群，但高度富集 对于肿瘤相关巨噬细胞。 因此，我们将研究这样的假设：骨转移代表细胞内在功能的顶峰。 驱动因素来自转移骨微环境中的转移细胞和肿瘤细胞外在因素。在 目标 1，我们将研究 CITED2 与 MYC 合作促进骨特异性的假设。在 同时，我们将研究与 RAS 通路激活相关的候选主调节因子 (MR) 阐明它们在骨转移中的潜在作用。在目标 2 中，我们将研究 ATAD2 是一个 雄激素剥夺背景下 MYC 的辅助因子，并阐明雄激素状态与 骨转移的演变和潜在机制。在目标 3 中，我们将研究细胞外在机制 在原发肿瘤和转移骨的微环境中，识别相关细胞群 与转移，评估其在骨转移中的功能作用，并确定骨的细胞外在驱动因素 转移。 整合：我们的研究与肿瘤微环境的研究高度互补 神经内分泌分化（项目 3）和肿瘤进展（项目 1）。候选监管机构的验证 人类骨转移需要核心A。此外，我们对单个骨转移的系统分析 细胞水平，补充项目 1 和 3 中的努力，而我们从这些数据中互惠互利的能力将 由 Core B 的数据管理组件启用。