Protein kinase C signaling in prostate cancer health disparities

前列腺癌健康差异中的蛋白激酶 C 信号传导

• 批准号: 10744533
• 负责人: MARCELO G. KAZANIETZ
• 金额: $ 48.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744533
• 关键词: Address; Affect; African American; African ancestry; Biological; Biological Factors; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Categories; Cells; Cessation of life; Collection; Data; Databases; Diagnosis; Diglycerides; Disease; Disease Progression; Disparity; Distant Metastasis; Epithelium; Etiology; European; Event; Exhibits; Foundations; Gene Expression; Generations; Genes; Genetic; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Gleason Grade for Prostate Cancer; Goals; Growth; Human; Human Resources; Hyperactivity; Immune; Immunocompetent; Immunohistochemistry; Impairment; Implant; Incidence; Inflammation Mediators; Inflammatory; Intrinsic factor; Invaded; Malignant neoplasm of prostate; Mediating; Mediator; Mesenchymal; Metastatic/Recurrent; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Organoids; Outcome; Pathway interactions; Phenotype; Phosphotransferases; Play; Population; Primary Neoplasm; Production; Prostatic Neoplasms; Protein Kinase C; RNA Interference; Race; Recurrent disease; Refractory; Regulation; Research Design; Resources; Role; Shapes; Signal Pathway; Signal Transduction; Socioeconomic Factors; Stains; Testing; Time; Tumor-infiltrating immune cells; Variant; cancer cell; cancer health disparity; castration resistant prostate cancer; cohort; cytokine; early onset; epithelial to mesenchymal transition; in vivo; insight; lifestyle factors; men; mortality; mouse model; neoplastic cell; novel marker; outcome disparities; overexpression; patient derived xenograft model; pharmacologic; programs; prostate cancer cell; prostate cancer cell line; prostate cancer model; prostate cancer progression; prostate carcinogenesis; racial difference; racial disparity; racial diversity; racial population; therapeutic target; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumorigenesis; tumorigenic

ABSTRACT Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the US, disproportionally affects men of African American (AA) descent, who exhibit greater incidence, faster disease progression and higher rate of mortality than men of European descent (EA). AA men are more likely to present high-grade disease and distant metastasis at the time of diagnosis. The drivers of this disparity are multifactorial, and include socioeconomic, lifestyle and biological factors. Current evidence suggests genetic alterations - such as changes in oncogenic and tumor suppressive genes associated with PCa progression - and the presence of a more inflammatory tumor microenvironment (TME) in prostate tumors from men of African descent as major underlying causes of this racial disparity. However, there is still a limited understanding of the molecular/signaling foundations behind the racial differences in PCa. Here, we identified the diacylglycerol-regulated kinase PKCa as a potential contributor towards racial disparities in PCa. We found PKCa to be aberrantly overexpressed in aggressive PCa cell lines as well as in human PCa. Interestingly, silencing PKCa expression from PCa cells impairs their invasive capacity as well as their ability to form tumors in mice. An in-depth RNA-Seq transcriptome analysis integrated with existing database inquires established PKCa as a crucial determinant for the expression of cytokines known to be dysregulated in prostate tumors from AA men. Most remarkably, expression analysis in patient-derived xenografts (PDXs) revealed higher PKCa levels in AA relative to EA prostate tumors, which associates with the expression of epithelial-to-mesenchymal transition (EMT) markers. This led us to hypothesize that excessive activation of PKCa signaling may contribute to racial disparities in PCa. In Aim 1 we will take advantage of a large collection of primary and metastatic human PCa tumors both from AA and EA men to test the hypothesis that there is disproportionate PKCa expression and/or activation in AA PCa. We will establish potential correlations with Gleason score, disease recurrence and metastatic disease in the available cohorts of AA and EA prostate tumors. In Aim 2 we will use both genetically engineered and syngeneic models towards the goal of establishing the in vivo functional relevance of PKCa in prostate tumorigenesis and metastasis. Racial- related cell/tumor growth differences will be established using EA vs. AA PDXs and organoids derived from these racially diverse set of PDXs. In Aim 3 we will pursue a thorough profiling of immune cell populations and cytokine expression in mouse prostate tumors upon inducible silencing of PKCa. Transcriptome signatures will be established both in mouse models as well as in EA vs. AA PDXs to identify racial differences in PKCa-driven gene expression. This will provide a comprehensive perspective on how tumor cell PKCa contributes to the generation of a pro-inflammatory tumorigenic state and an immunosuppressive landscape, and unearth associated differences based on racial distinction. Our studies should provide exceptionally valuable information on the oncogenic and metastatic pathways leading to racial disparities in PCa.

摘要 前列腺癌(PCA)是美国男性癌症相关死亡的第二大原因， 不成比例地影响非洲裔美国人(AA)男性，他们表现出更高的发病率和更快的疾病 进展和死亡率高于欧洲血统的男性(EA)。AA级男性更有可能出现在 确诊时的高度恶性疾病和远处转移。造成这种差异的原因是多方面的， 包括社会经济、生活方式和生物因素。目前的证据表明基因改变--比如 与前列腺癌进展相关的致癌和肿瘤抑制基因的变化-以及 非裔男性前列腺癌以炎症性更强的微环境(TME)为主 造成这种种族差异的根本原因。然而，对分子/信号转导的了解仍然有限。 PCA中种族差异背后的基础。在这里，我们鉴定了二酰甘油调节的蛋白激酶pkca 作为PCA中种族差异的潜在贡献者。我们发现PKCA在 侵袭性的前列腺癌细胞系以及人的前列腺癌。有趣的是，抑制前列腺癌细胞中PKCA的表达 削弱它们的侵袭能力以及它们在小鼠体内形成肿瘤的能力。一种深度RNA-Seq转录组 结合现有数据库查询的分析确定了PKCA是表达的关键决定因素 已知的在AA男性前列腺癌中调节失调的细胞因子。最值得注意的是，表情分析 在患者来源的异种移植物(PDX)中，相对于EA前列腺癌，AA中的PKCA水平更高 与上皮向间充质转化(EMT)标志物的表达有关。这就引出了我们的假设 PKCA信号的过度激活可能导致了PCa的种族差异。在目标1中，我们将采取 大量收集来自AA和EA男性的原发和转移性人前列腺癌的优势进行测试 假设在AA-PCa中存在不成比例的PKCA表达和/或激活。我们将建立 在可用队列中与Gleason评分、疾病复发和转移疾病的潜在相关性 AA和EA前列腺癌。在目标2中，我们将使用基因工程和同基因模型来实现 目的：建立PKCA在前列腺癌发生和转移中的体内功能相关性。种族- 相关的细胞/肿瘤生长差异将使用EA和AA PDX以及由此衍生的有机类化合物来建立 种族多元化的PDX系列。在目标3中，我们将对免疫细胞群体和细胞因子进行彻底的剖析 诱导沉默PKCA在小鼠前列腺癌中的表达。转录组签名将是 在小鼠模型以及电针与再生障碍性贫血PDX中建立，以确定PKCA驱动的种族差异 基因表达。这将提供一个关于肿瘤细胞PKCA如何在 促炎致癌状态和免疫抑制状态的产生，并发现 基于种族差异的相关差异。我们的研究应该提供特别有价值的信息 关于导致前列腺癌种族差异的致癌和转移途径。