Stromal Foxf2 suppresses prostate cancer progression

基质 Foxf2 抑制前列腺癌进展

基本信息

批准号：
10461677
负责人：
Li Xin
金额：
$ 49.36万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2022-07-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10461677
关键词：
Anatomy CRISPR/Cas technology Cancer Etiology Candidate Disease Gene Cessation of life ChIP-seq Data Disease Progression Down-Regulation Early Intervention Frequencies Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Gleason Grade for Prostate Cancer Goals Growth Human Immunocompetent Indolent Knock-out Laboratories Lead Left Malignant Neoplasms Malignant neoplasm of prostate Mediating Modeling Molecular Mus Mutagenesis Myeloid-derived suppressor cells NF-kappa B Nature Neuroendocrine Tumors Newly Diagnosed Pathologic Patients Peripheral Play Prognostic Marker Prostate Prostate Adenocarcinoma Recurrence Role Signal Transduction Stromal Cells Testing Therapeutic Therapeutic Intervention Tissues Transcriptional Activation United States Up-Regulation Xenograft procedure anti-CTLA4 anti-PD-1 base cancer initiation chemokine clinically significant cytokine genome-wide immune checkpoint blockade in vivo men mouse model novel overexpression overtreatment prostate cancer model prostate cancer progression recruit screening transcription factor transcriptome sequencing tumor tumor initiation tumor microenvironment tumor progression tumor xenograft

项目摘要

Project Summary Prostate cancer is the second leading cause of cancer related death in men in the United States. Many of the newly diagnosed patients are indolent and would not die from prostate cancer even if they are left untreated. But lack of reliable markers to identify such indolent tumors has led to overtreatment of patients. To minimize overtreatment, patients with a lower Gleason Score are put on active surveillance and are not treated unless there is sign of disease progression. Although such active surveillance can minimize over-treatment, it may miss the opportunity for early intervention of aggressive tumors. Therefore, understanding molecular mechanisms underlying the aggressive nature of prostate cancer and identifying prognostic markers to distinguish indolent from aggressive prostate cancers are of great clinical significance. Human prostate cancers mostly originate in the peripheral zone (PZ). In addition, transition zone (TZ) tumors are often associated with favorable pathological features and better recurrence-free survival. These observations lead to the hypothesis that the differences in tissue microenvironment between the two zones influence the frequency and aggressiveness of the resulting tumors. We compared gene expression profiles between TZ and PZ stroma by an RNA-seq analysis and identify the transcription factor FOXF2 as one of the top genes expressed at a higher level in TZ stromal cells. We demonstrated that elevated Foxf2 expression in prostate stromal cells suppressed growth of prostate cancer xenografts in vivo. In Aim1, we will use genetically engineered mouse models to confirm that stromal Foxf2- mediated signaling suppresses tumor progression. In Aim 2, we will investigate the molecular mechanisms through which stromal Foxf2 suppresses tumor progression. In Aim 3, we will investigate how stromal FOXF2 expression is regulated.

项目概要前列腺癌是美国男性癌症相关死亡的第二大原因。许多新诊断的患者性格惰性，即使不接受治疗也不会死于前列腺癌。但缺乏可靠的标记物来识别此类惰性肿瘤导致了对患者的过度治疗。尽量减少过度治疗，格里森评分较低的患者会受到积极监测，并且不会接受治疗，除非有疾病进展的迹象。虽然这种主动监测可以最大限度地减少过度治疗，但可能会错过早期干预侵袭性肿瘤的机会。因此，了解分子机制揭示前列腺癌的侵袭性本质并确定预后标志物以区分惰性从侵袭性前列腺癌中分离出来具有重要的临床意义。人类前列腺癌主要起源于外围区域（PZ）。此外，移行区（TZ）肿瘤通常与有利的病理学相关。特征和更好的无复发生存。这些观察结果得出这样的假设：两个区域之间的组织微环境影响所产生的频率和攻击性肿瘤。我们通过 RNA-seq 分析比较了 TZ 和 PZ 基质之间的基因表达谱，并确定转录因子 FOXF2 是 TZ 基质细胞中表达水平最高的基因之一。我们证明前列腺基质细胞中 Foxf2 表达升高可抑制前列腺癌的生长体内异种移植。在 Aim1 中，我们将使用基因工程小鼠模型来确认基质 Foxf2- 介导的信号传导抑制肿瘤进展。在目标2中，我们将研究分子机制基质 Foxf2 通过它抑制肿瘤进展。在目标 3 中，我们将研究基质 FOXF2 如何表达受到调节。