Elucidating and testing causal drivers of inflammation triggered prostatic early lesions
Elucidating and testing causal drivers of inflammation triggered prostatic early lesions
批准号:
10518915
负责人:
ANGELO Michael DE MARZO
金额:
$37.98万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-15 至 2027-08-31
关键词:
AcuteAdenocarcinomaArchitectureAttentionBenignCarcinomaCell NucleusCellsChromatinChronicCoupledDNADNA MethylationDNA Sequence AlterationDataDevelopmentEngineeringEpigenetic ProcessEpithelial CellsEquilibriumFrozen SectionsFutureGSTP1 geneGene ActivationGene ExpressionGenesGeneticGenomicsGrowthHumanHypermethylationImmuneImmune responseInflammationInflammation MediatorsInflammatoryInflammatory InfiltrateInterleukin-1 betaKnock-outLesionLymphoid CellMalignant NeoplasmsMalignant neoplasm of prostateMeasurementMetastatic Prostate CancerModelingMolecularMusMyeloid-derived suppressor cellsNeoplasmsPTGS2 genePatternPharmacologyPhasePositron-Emission TomographyProstateProstate AdenocarcinomaProstaticPublishingRNA InterferenceRegulatory T-LymphocyteSamplingSignal TransductionSmall Nuclear RNAStimulator of Interferon GenesStressTestingTissuesUp-RegulationVariantXCL1 genebasebiological adaptation to stresscancer initiationcell injuryepigenetic silencingepigenomicsgenome sequencingimaging agentimmune activationinhibitorlaser capture microdissectionmacrophagemouse modelmultimodalityneoplasticneoplastic cellnoveloverexpressionpromoterrecruittranscriptome sequencingwhole genome
中文摘要
项目概要/摘要:
我们提出,人类PIA中的炎性浸润反映了抗前列腺促炎免疫
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
PIA中常见的浸润通常在大多数前列腺癌中看不到。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,
启动步骤PIA真正的前肿瘤前体(PIN)和浸润性癌,这种免疫
回应必须取消。我们观察到人类应激反应和炎症基因的上调,
PIA腔上皮细胞。这些相同的基因(例如:GST P1,PTGS 2和LTF)在表观遗传学上是沉默的
在PIN和前列腺的早期和转移性浸润性腺癌中。这导致了一种潜在的分子
一种机制,其中一组在PIA中高度诱导表达的基因经历沉默,以允许细胞
出现PIN和浸润性癌。我们在这里表明,主要的炎症介质刺激因子,
干扰素基因(STING)在正常前列腺腔细胞中不存在,在中间腔细胞中高度诱导,
PIA中的细胞中表达,并且在绝大多数人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起始所需的。
第二,我们假设在PIA细胞的亚群中,STING(或其下游基因)的表观遗传沉默可能与PIA细胞的表观遗传沉默有关。
信号传导活性)导致免疫应答的抑制,通过允许它们
变成肿瘤细胞我们将测试这些假设如下。在具体目标1中,我们将遗传
并从药理学角度测试STING激活假说是否会导致急性和慢性炎症(PIA)
和PIN在小鼠前列腺中的作用,
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DNA甲基化进行全面表征,
小鼠和人类上皮细胞从前列腺炎性病变向前列腺增生转变过程中的表观基因组变化
肿瘤形成从机制上讲,我们假设STING(沿着许多其他应激和炎症诱导)
基因)在PIA向高级别PIN的过渡阶段被表观遗传学沉默。在具体目标3中,我们
假设在从试验场"毕业"的过程中,肿瘤细胞留下了促炎性细胞,
PIA中的微环境,并通过减少适应性免疫细胞来塑造微环境,
募集免疫抑制性髓样和淋巴样细胞(例如MDSC、M2巨噬细胞和TCFs),
帮助抑制癌症免疫反应。我们将定义的细胞组成和空间结构,
在小鼠和人类前列腺早期炎症病变的微环境中。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Admin-Core-001
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批准号:10933141
-
项目类别:
-
资助金额:$8.22万
-
财政年份:2023
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer
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批准号:10698119
-
项目类别:
-
资助金额:$148.56万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
Elucidating and testing causal drivers of inflammation triggered prostatic early lesions
-
批准号:10698123
-
项目类别:
-
资助金额:$28.8万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer
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批准号:10831131
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项目类别:
-
资助金额:$8.22万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
TBEL Administrative Core
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批准号:10518914
-
项目类别:
-
资助金额:$16.66万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer
-
批准号:10518913
-
项目类别:
-
资助金额:$155.89万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
TBEL Administrative Core
-
批准号:10698120
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项目类别:
-
资助金额:$38.1万
-
财政年份:2022
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry
-
批准号:10253255
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项目类别:
-
资助金额:$64.84万
-
财政年份:2015
-
负责人:ANGELO Michael DE MARZO
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依托单位:
Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry
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批准号:9565036
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项目类别:
-
资助金额:$32.7万
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财政年份:2015
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负责人:ANGELO Michael DE MARZO
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依托单位:
TISSUE MICROARRAY
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批准号:7304721
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项目类别:
-
资助金额:$8.38万
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财政年份:2006
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负责人:ANGELO Michael DE MARZO
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依托单位:
INFLAMMATION AND ATROPHY IN PROSTATE CARCINOGENESIS
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批准号:6284965
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项目类别:
-
资助金额:$31.19万
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财政年份:2001
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负责人:ANGELO Michael DE MARZO
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依托单位:
INFLAMMATION AND ATROPHY IN PROSTATE CARCINOGENESIS
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批准号:6633614
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项目类别:
-
资助金额:$28.45万
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财政年份:2001
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负责人:ANGELO Michael DE MARZO
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依托单位:
INFLAMMATION AND ATROPHY IN PROSTATE CARCINOGENESIS
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批准号:6514355
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项目类别:
-
资助金额:$28.57万
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财政年份:2001
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负责人:ANGELO Michael DE MARZO
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依托单位:
MOLECULAR PATHOLOGY OF STEM CELLS IN CANCER
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批准号:2681247
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项目类别:
-
资助金额:$7.98万
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财政年份:1998
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负责人:ANGELO Michael DE MARZO
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依托单位:
MOLECULAR PATHOLOGY OF STEM CELLS IN CANCER
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批准号:6522445
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项目类别:
-
资助金额:$9.06万
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财政年份:1998
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负责人:ANGELO Michael DE MARZO
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依托单位:
MOLECULAR PATHOLOGY OF STEM CELLS IN CANCER
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批准号:6376873
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项目类别:
-
资助金额:$9.06万
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财政年份:1998
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负责人:ANGELO Michael DE MARZO
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依托单位:
MOLECULAR PATHOLOGY OF STEM CELLS IN CANCER
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批准号:2896597
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项目类别:
-
资助金额:$7.98万
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财政年份:1998
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负责人:ANGELO Michael DE MARZO
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依托单位:
MOLECULAR PATHOLOGY OF STEM CELLS IN CANCER
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批准号:6174386
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项目类别:
-
资助金额:$9.06万
-
财政年份:1998
-
负责人:ANGELO Michael DE MARZO
-
依托单位:
TISSUE MICROARRAY
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批准号:8559548
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项目类别:
-
资助金额:$12.18万
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财政年份:1997
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负责人:ANGELO Michael DE MARZO
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依托单位:
TISSUE MICROARRAY
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批准号:8559765
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项目类别:
-
资助金额:$11.39万
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财政年份:--
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负责人:ANGELO Michael DE MARZO
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依托单位:
国内基金
海外基金
大肠癌发生机制的adenoma-adenocarcinoma pathway同serrated pathway的关系的研究
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批准号:30840003
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项目类别:专项基金项目
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资助金额:12.0万元
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批准年份:2008
-
负责人:焦宇飞
-
依托单位: