Stromal Foxf2 suppresses prostate cancer progression

基质 Foxf2 抑制前列腺癌进展

• 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
• 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

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.

项目摘要 前列腺癌是美国男性癌症相关死亡的第二大原因。许多人 新诊断的患者懒惰，即使不治疗也不会死于前列腺癌。但 缺乏可靠的标记物来识别这种惰性肿瘤，导致了患者的过度治疗。要最小化 过度治疗，格里森评分较低的患者被置于积极监测之下，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，但它可能会遗漏。 对侵袭性肿瘤进行早期干预的机会。因此，了解分子机制 前列腺癌侵袭性的基础和识别预后标记物以区分懒惰 侵袭性前列腺癌的发生具有重要的临床意义。人类前列腺癌主要起源于 外围区(PZ)。此外，移行区(TZ)肿瘤通常与良好的病理状态有关。 特点和更好的无复发存活率。这些观察结果导致了一种假设，即 两个区域之间的组织微环境影响由此产生的 肿瘤。我们通过rna-seq分析比较了TZ和PZ基质的基因表达谱，并鉴定了 转录因子FOXF2作为TOP基因之一，在TZ基质细胞中高水平表达。我们 前列腺癌间质细胞中Foxf2高表达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证实基质Foxf2- 介导的信号转导抑制肿瘤进展。在目标2中，我们将研究分子机制。 基质Foxf2通过其抑制肿瘤进展。在目标3中，我们将研究基质FOXF2是如何 表达是受调控的。