Spatial and mechanistic assessment of the role of stromal fibroblasts in driving emergence of aggressive prostate and bladder cancer

基质成纤维细胞在推动侵袭性前列腺癌和膀胱癌出现中的作用的空间和机制评估

基本信息

  • 批准号:
    10831131
  • 负责人:
  • 金额:
    $ 8.22万
  • 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
  • 起止时间:
    2022-09-15 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary: Epidemiological and pathological studies have implicated lifestyle, microbial, and environmental factors in prostate cancer etiology/risk. A potential link between these factors and prostate carcinogenesis is the presence of chronic inflammation associated with atrophy (PIA) in prostates of aging men. Yet, there is a paradox surrounding the role of the immune response in prostate cancer: “the inflammation paradox”. On one hand, inflammation may be a driver of carcinogenesis. On the other, the immune system is known to seek and destroy cancer cells. The majority prostate cancer lesions are “immune deserts”, and ICIs are ineffective in most cases. Why is there an evidently strong immune reaction in non- neoplastic regions in PIA, but a lack of a robust immune response in most prostate cancers? We hypothesize that chronic inflammation in PIA represents evidence of an innate immune response that drives carcinogenesis. However, in this inflammatory “proving ground”, only cells that can epigenetically switch off this response can emerge to become aggressive neoplastic precursors. We hypothesize that the paucity of immune infiltrates and lack of PD-L1, is evidence that prostate cancer cells develop a number of different mechanisms that evade anti-tumor adaptive immunity. We postulate that additional cell non- autonomous immune suppressive mechanisms enable disease progression. We propose 3 synergistic Research Projects (2 basic,1 translational) to mechanistically test key questions stemming from our “proving ground” hypothesis. In Proj 1 (Basic Science) we hypothesize that the STING induction in PIA drives acute and chronic inflammation, leading to cell injury/cell death and proliferation. Second, in a subset of PIA cells, epigenetic silencing of STING dampens of the immune response, allowing them to emerge as overt pre- neoplastic cells. We will test this in animal models and in translational studies employing annotated and molecularly characterized prostatectomies. The combination of PTEN loss and MYC copy number gain is an independent predictor of poor outcome in prostate cancer. We hypothesize that the combination of MYC and PTEN stimulates a cell non-autonomous immune evasion mechanism induced by the recruitment of immuno- suppressive myeloid cells, and fibroblast activation protein (FAP)-positive fibroblasts. Proj 2 (Basic Science) will test these hypotheses in animal models and in human tissues. Recently introduced imaging technologies have raised the hypothesis that PET/CT imaging results may be able to predict molecular and tumoral micro- environmental characteristics of aggressive prostate cancer. PET imaging for PSMA using PyL PET/CT has been FDA approved for imaging high risk men prior to prostatectomy. In Proj 3 (Translational) we employ PET/CT scanning for PSMA and combine this with mpMRI to address these hypotheses. Also in Proj 3 we will apply newly developed/developing PET imaging agents to non-invasively and longitudinally study the extent of M2 macrophages and cancer associated fibroblasts in our mouse prostate progression cancer models.
项目概述:流行病学和病理学研究涉及生活方式,微生物和

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Short-read aligner performance in germline variant identification.
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ANGELO Michael DE MARZO其他文献

ANGELO Michael DE MARZO的其他文献

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{{ truncateString('ANGELO Michael DE MARZO', 18)}}的其他基金

Admin-Core-001
管理核心-001
  • 批准号:
    10933141
  • 财政年份:
    2023
  • 资助金额:
    $ 8.22万
  • 项目类别:
Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer
前列腺炎性病变是侵袭性前列腺癌发展的试验场
  • 批准号:
    10698119
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
TBEL Administrative Core
TBEL 行政核心
  • 批准号:
    10518914
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
Prostate inflammatory lesions as a proving ground for development of aggressive prostate cancer
前列腺炎性病变是侵袭性前列腺癌发展的试验场
  • 批准号:
    10518913
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
TBEL Administrative Core
TBEL 行政核心
  • 批准号:
    10698120
  • 财政年份:
    2022
  • 资助金额:
    $ 8.22万
  • 项目类别:
Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry
多学科综合基因组方法区分欧洲和非洲血统男性的致命性前列腺癌和惰性前列腺癌
  • 批准号:
    10253255
  • 财政年份:
    2015
  • 资助金额:
    $ 8.22万
  • 项目类别:
Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry
多学科综合基因组方法区分欧洲和非洲血统男性的致命性前列腺癌和惰性前列腺癌
  • 批准号:
    9565036
  • 财政年份:
    2015
  • 资助金额:
    $ 8.22万
  • 项目类别:
TISSUE MICROARRAY
组织微阵列
  • 批准号:
    7304721
  • 财政年份:
    2006
  • 资助金额:
    $ 8.22万
  • 项目类别:

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