Role of Gastrokine 2 in pancreatic cancer development

Gastrokine 2 在胰腺癌发展中的作用

基本信息

批准号：
10752479
负责人：
Whitney Jean Bell
金额：
$ 3.92万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2023-07-12 至 2025-07-11
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752479
关键词：
Address Adult Affect Anti-Inflammatory Agents Biological Assay Cancer Etiology Cell Differentiation process Cell Line Cell Proliferation Cells Cellular Morphology Cessation of life Color Confocal Microscopy Data Development Diagnosis Differentiation and Growth Disease Disease Progression Doxycycline Duct (organ) structure Epithelial Cells Epithelium Etiology Event Family member Gene Expression Genes Goals Histologic Homeostasis Human Immunofluorescence Immunologic Immunohistochemistry In Vitro Interleukin-12 Invaded KRAS oncogenesis Kinetics Knowledge Lesion Lesion by Stage Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mesenchymal Metaplastic Cell Metaplastic Epithelial Cell Modeling Molecular Biology Techniques Mucins Mucous Membrane Mus Neoplasm Metastasis Operative Surgical Procedures Organoids Pancreas Pancreatic Diseases Pancreatic Ductal Adenocarcinoma Pathological Staging Pattern Phenotype Play Population Proteins Regulation Reporting Research Research Proposals Role Signal Pathway Signal Transduction Source Specific qualifier value Staging Stains Stomach Surface Survival Rate System TFF1 gene TP53 gene Testing Therapeutic Intervention Training Tumor Subtype Tumor Volume Tumor Weights United States Up-Regulation Western Blotting Woman Work axon guidance biomarker development cancer cell differentiation cancer initiation cytokine differential expression experimental study gastric foveola histological stains immunocytochemistry in vivo inducible gene expression inhibitor insight interleukin-23 knock-down loss of function malignant stomach neoplasm men molecular subtypes mutant neoplastic neoplastic cell pancreatic cancer cells pancreatic neoplasm pancreatic tumorigenesis patient prognosis premalignant programs protein expression single-cell RNA sequencing small hairpin RNA statistics transcriptome sequencing treatment response tumor tumor growth tumor progression tumorigenic

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest adult cancers with a 5-year survival rate of only 11% and is one of the top five leading causes of cancer-related deaths for men and women in the United States. These dire statistics underscore the need for a better understanding of the mechanisms that promote pancreatic cancer initiation and progression. Recent studies have begun to show that metaplastic epithelial differentiation in pancreatic cancer can significantly impact disease progression. Our preliminary data from ongoing studies investigating the role of cytokines IL-12/IL-23 in pancreatic cancer cell differentiation showed that gain of aggressive epithelial to mesenchymal-like phenotype is associated with the concurrent loss of gastric lineage genes, including Gastrokine 2 (Gkn2). Gkn2 is abundantly expressed by normal stomach epithelial cells, plays an anti-inflammatory role in gastric epithelial homeostasis. Recently, Gkn2 and its family member Gkn1 have been shown to be de novo upregulated in metaplastic epithelial cells in pancreatic cancer. However, the functional roles of gastrokines in pancreatic tumorigenesis remain unclear. The goals of this proposal are to elucidate the kinetics, cellular source, and driver(s) of de novo Gkn2 expression in pancreatic neoplasia, as well as determine the functional role of Gkn2 in pancreatic cancer development. To achieve these goals, in Aim 1, we will determine the expression pattern and cellular identity of Gkn2-positive cells, as well as understand how oncogenic Kras and/or Src signaling may contribute to the expression of Gkn2 in pancreatic epithelial cells. In Aim 2, we will investigate the functional role of Gkn2 in pancreatic tumor growth, tumor cell differentiation, and invasion. Specifically, we will utilize reversible Gkn2 knockdown systems to determine its contribution to the growth and differentiation of Kras-transformed epithelial cells in pancreatic cancer. Our proposed research will utilize state-of-the art models to provide an understanding of how a gastric identity gene program emerges early in transformed pancreatic epithelium and acts as a potential impediment to the aggressive progression of cancer.

抽象的胰腺导管腺癌 (PDAC) 是最致命的成人癌症之一，其 5 年生存率为仅 11%，是美国男性和女性癌症相关死亡的前五位主要原因之一国家。这些可怕的统计数据强调需要更好地了解促进胰腺癌的发生和进展。最近的研究开始表明化生上皮胰腺癌的分化可以显着影响疾病进展。我们的初步数据来自正在进行的研究调查细胞因子 IL-12/IL-23 在胰腺癌细胞分化中的作用表明侵袭性上皮细胞向间充质细胞样表型的获得与胃功能的同时丧失相关谱系基因，包括 Gastrokine 2 (Gkn2)。 Gkn2 在正常胃上皮细胞中大量表达，在胃上皮稳态中发挥抗炎作用。最近，Gkn2 及其家族成员 Gkn1 已被证明在胰腺癌化生上皮细胞中从头上调。然而，胃因子在胰腺肿瘤发生中的功能作用仍不清楚。该提案的目标是阐明胰腺肿瘤中 Gkn2 从头表达的动力学、细胞来源和驱动因素确定 Gkn2 在胰腺癌发展中的功能作用。为了实现这些目标，在目标 1 中，我们将确定 Gkn2 阳性细胞的表达模式和细胞身份，并了解如何致癌的 Kras 和/或 Src 信号传导可能有助于 Gkn2 在胰腺上皮细胞中的表达。在目标 2，我们将研究 Gkn2 在胰腺肿瘤生长、肿瘤细胞分化和入侵。具体来说，我们将利用可逆的 Gkn2 敲低系统来确定其对 Kras 转化的上皮细胞在胰腺癌中的生长和分化。我们提出的研究将利用最先进的模型来了解胃身份基因程序如何早期出现存在于转化的胰腺上皮中，并且是癌症侵袭性进展的潜在障碍。