Exploring the role of stromal GLI proteins in Pancreatic Ductal Adenocarcinoma

探索基质 GLI 蛋白在胰管腺癌中的作用

• 批准号: 9760578
• 负责人: Michael Kemper Scales
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760578
• 关键词: Address; Anger; Automobile Driving; Cancer Etiology; Cancer cell line; Cessation of life; Data; Detection; Development; Diagnosis; Disease; Dose; Epithelial; Erinaceidae; Family; Fibroblasts; GLI Family Protein; GLI gene; GLI2 gene; GLI3 gene; Genes; Genetic Transcription; Growth; Homeostasis; Human; In Situ; Individual; Injections; Knockout Mice; LacZ Genes; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; Mutant Strains Mice; Neoplasm Metastasis; Neoplasms; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Play; Premalignant; Process; Production; Proteins; Regulation; Reporter; Research; Role; Signal Transduction; Stains; Testing; Therapeutic; Tissues; Transcription Coactivator; Tumor-Derived; Western Blotting; base; beta-Galactosidase; carcinogenesis; effective therapy; experimental study; human disease; ineffective therapies; insight; novel; novel therapeutics; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; paracrine; response; smoothened signaling pathway; stem; transcription factor; tumor; tumor growth

ABSTRACT Pancreatic Ductal Adenocarcinoma (PDA) remains one of the deadliest cancers, with minimal therapeutic improvement over the last 40 years. This lack of effective therapies is due, in part, to a poor understanding of the signaling mechanisms driving PDA. Our lab and others have identified an aberrant increase in Hedgehog (HH) ligand production during PDA progression that signals to the surrounding tumor stroma (Thayer and Pasca di Magliano et al., 2003; Berman et al., 2003; Jones et al., 2008; Theunissen & de Sauvage, 2009). Disruption of HH signaling influences PDA progression, although the exact effect is controversial. This controversy stems, in part, from a poor understanding of the mechanisms mediating HH signaling in PDA. Prior research from our lab has demonstrated that HH signaling restrains PDA tumor growth in a dose-dependent manner (Mathew et al., 2014). However, the mechanisms that dictate the levels of HH signaling in PDA are poorly understood. In development and other forms of HH-driven disease, the GLI family of HH transcription factors (GLI1, GLI2, GLI3) plays a crucial role in mediating downstream HH signaling. However, the role of GLI1-3 in PDA remains largely unknown. My data indicate that Gli1-3 are expressed in the healthy pancreas, and that this expression is restricted to pancreatic fibroblasts. In addition, I have determined that the expression Gli1-3 expands throughout the pancreatic stroma during the formation of precancerous lesions. Based on these preliminary data, I hypothesize that GLI1-3 restrict PDA tumor growth by regulating stromal HH signaling. To test this hypothesis, I will first determine the expression and protein processing of GLI1-3 in the context of metastatic pancreatic cancer. I will also evaluate the expression of HH target genes at different stages of PDA progression, to correlate GLI1-3 expression and processing with the level of HH pathway activity. To define the role of stromal GLI proteins in PDA, I will eliminate Gli expression in pancreatic fibroblasts and determine the effect on pancreatic cancer growth in situ. These experiments will provide mechanistic insight into our understanding of HH signaling in PDA progression, and will reveal novel roles for GLI proteins in this deadly disease.

摘要 胰腺导管腺癌（PDA）仍然是最致命的癌症之一， 在过去的40年里，缺乏有效的治疗方法，部分原因是对以下因素的了解不足 驱动PDA的信号机制。我们的实验室和其他实验室已经发现了刺猬的异常增加 (HH)PDA进展过程中产生的配体向周围的肿瘤间质发出信号（Thayer和Pasca di Magliano等人，2003; Berman等人，2003; Jones等人，2008;泰尼森& de Sauvage，2009）。中断 HH信号的影响PDA的进展，虽然确切的效果是有争议的。这场争论， 部分原因是对PDA中介导HH信号传导的机制缺乏了解。我们之前的研究 实验室已经证明HH信号以剂量依赖性方式抑制PDA肿瘤生长（Mathew et 例如，2014年）。然而，在PDA中决定HH信号水平的机制知之甚少。在 HH驱动的疾病的发展和其他形式，HH转录因子的GLI家族（GLI 1，GLI 2，GLI 3） 在介导下游HH信号传导中起关键作用。然而，GLI 1 -3在PDA中的作用仍然很大程度上是 未知我的数据表明，Gli 1 -3在健康胰腺中表达，并且这种表达在正常胰腺中表达。 仅限于胰腺成纤维细胞。此外，我已经确定，表达Gli 1 -3扩展到整个 胰腺癌前病变形成期间的间质。根据这些初步数据，我 假设GLI 1 -3通过调节间质HH信号传导限制PDA肿瘤生长。为了验证这一 假设，我将首先确定GLI 1 -3的表达和蛋白质加工的背景下，转移 胰腺癌我还将评估HH靶基因在PDA进展的不同阶段的表达， 将GLI 1 -3表达和加工与HH途径活性水平相关联。为了明确基质的作用， GLI蛋白在PDA中的表达，我将消除胰腺成纤维细胞中的Gli表达，并确定对PDA的影响。 胰腺癌原位生长。这些实验将为我们理解 HH信号在PDA进展中的作用，并将揭示GLI蛋白在这种致命疾病中的新作用。