Elucidating and testing causal drivers of inflammation triggered prostatic early lesions

阐明和测试炎症引发前列腺早期病变的因果驱动因素

• 批准号: 10518915
• 负责人: ANGELO Michael DE MARZO
• 金额: $ 37.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518915
• 关键词: Acute; Adenocarcinoma; Architecture; Attention; Benign; Carcinoma; Cell Nucleus; Cells; Chromatin; Chronic; Coupled; DNA; DNA Methylation; DNA Sequence Alteration; Data; Development; Engineering; Epigenetic Process; Epithelial Cells; Equilibrium; Frozen Sections; Future; GSTP1 gene; Gene Activation; Gene Expression; Genes; Genetic; Genomics; Growth; Human; Hypermethylation; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Interleukin-1 beta; Knock-out; Lesion; Lymphoid Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metastatic Prostate Cancer; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Neoplasms; PTGS2 gene; Pattern; Pharmacology; Phase; Positron-Emission Tomography; Prostate; Prostate Adenocarcinoma; Prostatic; Publishing; RNA Interference; Regulatory T-Lymphocyte; Sampling; Signal Transduction; Small Nuclear RNA; Stimulator of Interferon Genes; Stress; Testing; Tissues; Up-Regulation; Variant; XCL1 gene; base; biological adaptation to stress; cancer initiation; cell injury; epigenetic silencing; epigenomics; genome sequencing; imaging agent; immune activation; inhibitor; laser capture microdissection; macrophage; mouse model; multimodality; neoplastic; neoplastic cell; novel; overexpression; promoter; recruit; transcriptome sequencing; whole genome

Project Summary/Abstract: We have proposed that inflammatory infiltrates in human PIA reflect an anti-prostatic pro-inflammatory immune response that serves as a hotbed for cancer initiation. Interestingly, the acute and chronic inflammatory cell infiltrates common in PIA are generally not seen in most prostate cancers. These observations have prompted our proving ground hypothesis which suggests that in order for prostate cancer to develop past these initiated steps in PIA to bona fide pre-neoplastic precursor (PIN) and to invasive carcinoma, this immune response must be abrogated. We observed upregulation of stress-response and inflammatory genes in human PIA luminal epithelial cells. These same genes (examples: GSTP1, PTGS2, and LTF ) are epigenetically silenced in PIN and early and metastatic invasive adenocarcinoma of the prostate. This led to a potential molecular mechanism in which a set of genes whose expression is highly induced in PIA undergo silencing to allow cells to emerge as PIN and invasive carcinoma. We show here that the major inflammatory mediator Stimulator of Interferon Genes (STING) is absent in normal prostate luminal cells, is highly induced in intermediate luminal cells in PIA, and is not expressed in the vast majority of human PIN and adenocarcinomas. We hypothesize STING expression in PIA luminal cells is required for inflammation, cell injury, and the prostate cancer initiation. Second, we hypothesize that in a subset of PIA cells, epigenetic silencing of STING (or of its downstream signaling activity) results in dampening of the immune response, imparting a growth advantage by allowing them to emerge as neoplastic cells. We will test these hypotheses in as follows. In Specific Aim 1 we will genetically and pharmacologically test the STING activation hypothesis for developing acute and chronic inflammation, PIA and PIN in the mouse prostate using our unique mouse model of IL1-beta induced prostatic inflammation and PIA progressing to PIN (IMPI mice). In Specific Aim 2 we will test the “epigenetic silencing of induced genes” hypothesis in human samples by performing a comprehensive characterization of DNA-methylation based epigenomic changes in mouse and human epithelial cells in the transitions from prostatic inflammatory lesions to neoplasia. Mechanistically, we hypothesize that STING (along with many other stress and inflammation induced genes) is epigenetically silenced at the transition stage of PIA to high grade PIN. In Specific Aim 3, we hypothesize that in "graduating" from the proving ground, neoplastic cells leave behind the pro-inflammatory microenvironment in PIA, and sculpt a microenvironment with reduced adaptive immune cells through recruitment of immune suppressive myeloid and lymphoid cells (e.g. MDSCs, M2 macrophages and Tregs) that help quell the cancer immune response. We will define the cellular composition and spatial architecture of microenvironment in mouse and human early precursor prostatic inflammatory lesions.

项目摘要/摘要： 我们提出，人 PIA 中的炎症浸润反映了抗前列腺促炎免疫 反应成为癌症发生的温床。有趣的是，急性和慢性炎症细胞 PIA 中常见的浸润在大多数前列腺癌中通常不可见。这些观察结果促使 我们的试验场假设表明，为了使前列腺癌发展超过这些 在 PIA 中启动了针对真正的肿瘤前体 (PIN) 和侵袭性癌的步骤，这种免疫 回应必须被废除。我们观察到人类应激反应和炎症基因的上调 PIA 管腔上皮细胞。这些相同的基因（例如：GSTP1、PTGS2 和 LTF）在表观遗传上被沉默 PIN 和前列腺的早期和转移性侵袭性腺癌。这导致了潜在的分子 一组在 PIA 中表达被高度诱导的基因经历沉默以允许细胞 表现为 PIN 和浸润性癌。我们在这里展示了主要的炎症介质刺激物 干扰素基因 (STING) 在正常前列腺管腔细胞中不存在，在中间管腔细胞中高度诱导 在 PIA 细胞中表达，并且在绝大多数人类 PIN 和腺癌中不表达。我们假设 PIA 管腔细胞中的 STING 表达是炎症、细胞损伤和前列腺癌发生所必需的。 其次，我们假设在 PIA 细胞的一个子集中，STING（或其下游）的表观遗传沉默 信号活动）导致免疫反应减弱，通过允许它们赋予生长优势 以肿瘤细胞的形式出现。我们将如下测试这些假设。在具体目标 1 中，我们将从基因角度 并药理学测试 STING 激活假说以发展急性和慢性炎症、PIA 和 PIN 在小鼠前列腺中使用我们独特的 IL1-β 诱导前列腺炎症小鼠模型 PIA 进展为 PIN（IMPI 小鼠）。在具体目标 2 中，我们将测试“诱导基因的表观遗传沉默” 通过对基于 DNA 甲基化的全面表征，在人类样本中提出假设 小鼠和人类上皮细胞在从前列腺炎症病变到前列腺炎转变过程中的表观基因组变化 瘤形成。从机制上讲，我们假设 STING（以及许多其他压力和炎症引起的） 基因）在 PIA 到高级 PIN 的过渡阶段被表观遗传沉默。在具体目标 3 中，我们 假设在从试验场“毕业”时，肿瘤细胞留下了促炎细胞 PIA 中的微环境，并通过减少适应性免疫细胞来塑造微环境 招募免疫抑制性骨髓细胞和淋巴细胞（例如 MDSC、M2 巨噬细胞和 Tregs） 帮助平息癌症免疫反应。我们将定义细胞组成和空间结构 小鼠和人类早期前体前列腺炎症病变的微环境。