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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涉及生活方式，微生物，前列腺癌病因/风险的环境因素。这些因素和前列腺之间的潜在联系前列腺癌的一个重要原因是老年前列腺中存在与萎缩相关的慢性炎症（PIA 男人然而，围绕免疫反应在前列腺癌中的作用存在一个悖论：“免疫反应在前列腺癌中的作用炎症悖论”。一方面，炎症可能是致癌的驱动因素。另一方面是已知免疫系统寻找并摧毁癌细胞。大多数前列腺癌病变是“免疫性的”， “沙漠”，而ICI在大多数情况下无效。为什么在非- PIA中的肿瘤区域，但大多数前列腺癌缺乏强大的免疫反应？我们假设 PIA的慢性炎症代表了先天免疫反应的证据，致癌作用然而，在这个炎症的“试验场”，只有细胞，关闭这种反应可能成为侵袭性肿瘤前体。我们假设免疫浸润的缺乏和PD-L1的缺乏证明前列腺癌细胞产生了许多逃避抗肿瘤适应性免疫的不同机制。我们假设额外的细胞非- 自主免疫抑制机制使疾病进展。我们建议3协同研究项目（2个基础，1个翻译），以机械地测试我们的“证明”产生的关键问题地面”的假设。在项目1（基础科学）中，我们假设PIA中的STING诱导驱动急性和慢性炎症，导致细胞损伤/细胞死亡和增殖。其次，在PIA细胞的子集中， STING的表观遗传沉默抑制了免疫反应，使它们以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，以分子为特征的切除术。PTEN丢失和MYC拷贝数增加的组合是一个新的基因。前列腺癌预后不良独立预测因子。我们假设MYC和 PTEN刺激细胞非自主性免疫逃避机制，该机制由免疫应答的募集诱导。抑制性骨髓细胞和成纤维细胞活化蛋白（FAP）阳性成纤维细胞。项目2（基础科学）将在动物模型和人体组织中测试这些假设。最近推出的成像技术提出了PET/CT成像结果可能能够预测分子和肿瘤微- 侵袭性前列腺癌的环境特征。使用PyL PET/CT进行PSMA的PET成像，被FDA批准用于前列腺切除术前的高风险男性成像。在项目3（翻译）中，我们采用 PSMA的PET/CT扫描和联合收割机将其与mpMRI结合以解决这些假设。此外，在项目3中，我们将应用新开发的/正在开发的PET显像剂，以非侵入性和纵向研究 M2巨噬细胞和癌症相关的成纤维细胞在我们的小鼠前列腺进展癌症模型。