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: 10698123
• 负责人: ANGELO Michael DE MARZO
• 金额: $ 28.8万
• 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/10698123
• 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; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Interleukin-1 beta; Knock-out; Lesion; Lymphoid Cell; Macrophage; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Metastatic Prostate Cancer; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Neoplasms; PTGS2 gene; Pattern; Phase; Positron-Emission Tomography; Prostate; Prostate Adenocarcinoma; Prostatic; Publishing; RNA Interference; Regulatory T-Lymphocyte; Sampling; Signal Transduction; Stimulator of Interferon Genes; Stress; Testing; Tissues; Up-Regulation; Variant; XCL1 gene; biological adaptation to stress; cancer initiation; cell injury; epigenetic silencing; epigenomics; genome sequencing; imaging agent; immune activation; inhibitor; laser capture microdissection; mouse model; multimodality; neoplastic; neoplastic cell; novel; overexpression; pharmacologic; promoter; recruit; single nucleus RNA-sequencing; synergism; 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中的炎症性浸润反映了抗促进性促炎性免疫 作为癌症开始的温床的反应。有趣的是，急性和慢性炎症细胞 通常在大多数前列腺取消PIA中常见的PIA浸润。这些观察提示了 我们的证明地面假设表明，为了使前列腺癌发展到这些假设 在PIA中开始的步骤至真正的肿瘤前前体（PIN）和侵入性癌，这种免疫 响应必须被废除。我们观察到人类应力反应和炎症基因的上调 PIA腔腔上皮细胞。这些相同的基因（示例：GSTP1，PTGS2和LTF）在表观遗传上沉默 在PIN和前列腺的早期和转移性浸润性腺癌中。这导致了潜在的分子 在PIA中高度诱导的一组基因进行沉默以允许细胞的机制 出现为销钉和浸润性癌。我们在这里表明，主要的炎症介质刺激器 在正常前列腺腔细胞中不存在干扰素基因（STING），在中间腔中高度诱导 PIA中的细胞，在绝大多数人销和腺癌中不表达。我们假设 在感染，细胞损伤和前列腺癌的启动中，PIA腔细胞中的刺激表达是必需的。 其次，我们假设在PIA细胞的子集中，刺痛的表观遗传沉默（或其下游的 信号传导活性）导致免疫反应减弱，从而通过允许它们赋予生长优势 作为肿瘤细胞出现。我们将在如下测试这些假设。在特定目标1中，我们将一般 并从药理测试刺激性激活假说，用于发展急性和慢性感染PIA 使用我们独特的IL1-β诱导前列腺注射和 PIA发展到销钉（Impi小鼠）。在特定目标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，人类样品中的假设 小鼠和人类上皮细胞的表观基因组变化从前列腺炎症病变过渡到 肿瘤。从机械上讲，我们假设刺痛（以及许多其他压力和炎症引起的 基因）在PIA过渡到高级引脚的过渡阶段表观遗传沉默。在特定的目标3中，我们 假设在从试验场“毕业”中，肿瘤细胞留下了促炎性的细胞 PIA中的微环境，并通过降低适应性免疫球的微环境雕刻 募集免疫抑制性髓样和淋巴样细胞（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 小鼠和人类早期前列腺前列腺炎症病变中的微环境。