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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：
ANGELO Michael DE MARZO
金额：
$ 8.22万
依托单位：
JOHNS HOPKINS UNIVERSITY
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与生活方式、微生物和前列腺癌病因学/风险中的环境因素这些因素与前列腺癌之间的潜在联系癌变是指与萎缩相关的慢性炎症(PIA)在老年前列腺中的存在。男人。然而，围绕着免疫反应在前列腺癌中的作用存在着一个悖论： “炎症悖论”。一方面，炎症可能是癌症发生的驱动因素。另一方面，众所周知，免疫系统寻找并摧毁癌细胞。大多数前列腺癌病变是“免疫的” 沙漠“和ICIS在大多数情况下都是无效的。为什么在非霍奇金淋巴瘤中有明显强烈的免疫反应 PIA中的肿瘤区，但大多数前列腺癌缺乏强大的免疫反应？我们假设 PIA的慢性炎症是先天免疫反应的证据，这种免疫反应促使致癌。然而，在这片炎症性的“试验田”中，只有表观遗传学上能够关闭这种反应可能会成为侵袭性肿瘤的先兆。我们假设免疫浸润物的缺乏和PD-L1的缺乏，是前列腺癌细胞发展成许多逃避抗肿瘤获得性免疫的不同机制。我们假设额外的细胞不是自主免疫抑制机制使疾病得以进展。我们提出了三个协同效应研究项目(2个基本项目，1个翻译项目)，以机械方式测试由我们的“证明”产生的关键问题 “地面”假设。在项目1(基础科学)中，我们假设PIA中的刺痛诱导会导致急性和慢性炎症，导致细胞损伤/细胞死亡和增殖。其次，在PIA细胞的子集中，表观遗传沉默抑制免疫反应的刺痛，使它们成为明显的前... 肿瘤细胞。我们将在动物模型和翻译研究中测试这一点，使用带注释和前列腺摘除手术的分子特征。PTEN损失和MYC拷贝数增加的组合是一个前列腺癌预后不良的独立预测因子。我们假设MYC和MYC的结合 PTEN刺激细胞非自主免疫逃逸机制，通过募集免疫- 抑制性髓系细胞和成纤维细胞激活蛋白(FAP)阳性的成纤维细胞。项目2(基础科学) 将在动物模型和人体组织中检验这些假说。最近引进的成像技术提出了一种假设，即PET/CT成像结果可能能够预测分子和肿瘤的微观侵袭性前列腺癌的环境特征。PYL PET/CT对PSMA的PET成像 FDA批准在前列腺切除术前对高危男性进行成像。在项目3(翻译)中，我们使用对PSMA进行PET/CT扫描，并结合mpMRI来解决这些假说。同样在项目3中，我们将应用新开发的PET显像剂进行无创性和纵向研究小鼠前列腺癌模型中的M2巨噬细胞和肿瘤相关成纤维细胞。