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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的前列腺癌（PCA）是美国男性与癌症相关死亡的第二大原因，不成比例地影响非裔美国人（AA）血统的人，他们表现出更大，更快的疾病比欧洲血统的男性（EA）的进展和更高的死亡率。男人更有可能出现诊断时的高级疾病和遥远的转移。这种差异的驱动力是多因素的，并包括社会经济，生活方式和生物学因素。当前的证据表明遗传改变 - 这样随着与PCA进展相关的致癌基因和肿瘤抑制基因的变化，并且存在来自非洲血统的前列腺肿瘤中的炎症性肿瘤微环境（TME）是主要的这种种族差异的根本原因。但是，对分子/信号传导的理解仍然有限 PCA种族差异背后的基础。在这里，我们确定了二酰基甘油调节的激酶PKCA 作为PCA种族差异的潜在贡献者。我们发现PKCA异常过表达侵略性PCA细胞系以及人PCA。有趣的是，使PCA细胞的PKCA表达沉默损害其侵入能力以及在小鼠中形成肿瘤的能力。深度RNA-Seq转录组与现有数据库询问集成的分析已建立的PKCA作为表达式的至关重要的决定因素来自AA男性的前列腺肿瘤中已知的细胞因子的失调。最引人注目的是表达分析在患者衍生的异种移植物（PDX）中，相对于EA前列腺肿瘤，AA的PKCA水平较高，而PROSTATE肿瘤与上皮到间质转变（EMT）标记的表达相关。这导致我们假设 PKCA信号的过度激活可能导致PCA的种族差异。在目标1中，我们将采取从AA和EA男士进行的大量原发性和转移性人PCA肿瘤的优势进行测试 AA PCA中的PKCA表达和/或激活的假设是。我们将建立与格里森评分，疾病复发和转移性疾病的潜在相关性 AA和EA前列腺肿瘤。在AIM 2中，我们将使用基因工程和合成模型用于建立PKCA在前列腺肿瘤发生和转移中的体内功能相关性的目标。种族将使用EA与AA PDXS建立相关的细胞/肿瘤生长差异种族多样的PDX集。在AIM 3中，我们将详细介绍免疫细胞群体和细胞因子小鼠前列腺肿瘤的表达在诱导型PKCA时表达。转录组签名将是在鼠标模型和EA与AA PDX中建立，以识别PKCA驱动的种族差异基因表达。这将提供有关肿瘤细胞PKCA如何贡献肿瘤细胞的全面观点产生促炎性肿瘤状态和免疫抑制景观，并发掘基于种族区别的相关差异。我们的研究应提供异常有价值的信息关于导致PCA种族差异的肿瘤和转移途径。