The CCK-B receptor signaling pathway as a driver of pancreatic cellular plasticity and carcinogenesis

CCK-B 受体信号通路作为胰腺细胞可塑性和癌变的驱动因素

基本信息

批准号：
10578371
负责人：
Mariaelena Pierobon
金额：
$ 60.64万
依托单位：
GEORGETOWN UNIVERSITY
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：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10578371
关键词：
Acinar Cell Adult Affect Cancer Etiology Cell Proliferation Cells Cessation of life Characteristics Cholecystokinin A Receptor Cholecystokinin B Receptor Cholecystokinin Receptor Chronic Clinical Collagen Collagen Type I Cytometry Development Disease Duct (organ) structure Ductal Epithelial Cell Epithelial Cells Event Extracellular Matrix Fibroblasts Fibrosis G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Goals Growth Factor Human Immune In Vitro Incidence Inflammation Inflammatory Injury Investigation KRAS2 gene Knock-out Knockout Mice Lasers Lesion Macrophage Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Metaplasia Microdissection Modeling Molecular Mus Natural regeneration Oncogenic Organ Outcome Pancreas Pancreatic Intraepithelial Neoplasia Pancreatitis Pathway interactions Phase Phase I Clinical Trials Phenotype Process Production Proglumide Protein Array Proteins Receptor Cross-Talk Recovery Research Risk Role Safety Signal Pathway Stimulus Stress Techniques Testing Tissues Wild Type Mouse advanced disease antagonist cancer risk carcinogenesis carcinogenicity cell injury cell motility cell type chemokine chemokine receptor chronic pancreatitis cytokine differential expression human subject insight migration mouse model mutant neutrophil new therapeutic target novel overexpression pancreas development pancreatic neoplasm pancreatic stellate cell pancreatic tumorigenesis premalignant prevent progenitor programs receptor recruit response stellate cell therapeutic target transcriptome sequencing transdifferentiation tumor microenvironment

项目摘要

Abstract It has become well recognized that inflammation from chronic pancreatitis is associated an 8-fold increased risk for the development of pancreatic cancer. When cells are injured or stressed, they can transform to a cell with a different phenotype through a process called metaplasia. In the pancreas, acinar-ductal metaplasia (ADM) occurs with pancreatitis and this process is usually reversible. However, with chronic inflammation or maturation arrest, the ductal phenotype cells do not reverse to their normal acinar phenotype but may progress to pancreatic intraepithelial neoplasia (PanINs) and pancreatic cancer. There is a gap in our understanding of the mechanisms involved in this recovery or loss of the ability to recover. Our lab has been studying G-protein coupled receptors and found that the cholecystokinin-B receptor (CCK-BR) that is found in ductal cells but not acinar cells becomes expressed during chronic pancreatitis and PanIN formation, and is markedly over-expressed in pancreatic cancer. Treatment with a CCK-receptor antagonist, proglumide, hastens recovery of ADM, decreases inflammation, and restores the pancreas to a normal phenotype. In more advanced disease with PanINs or with pancreatic cancer, proglumide treatment also alters the pancreas extracellular matrix or tumor microenvironment, by decreasing collagen production from pancreatic stellate cells or cancer-associated fibroblasts and changing the immune cell signature to a more normal phenotype. We hypothesize that the CCK-BR signaling pathway is a novel and key pathway in pancreatic plasticity; strategies to suppress this pathway will decrease pancreatic cancer. Proglumide has already been tested in human subjects in a Phase 1 clinical trial and deemed to have a broad safety profile. In this proposal we will study the role of proglumide and the CCK-BR in pancreatic cell plasticity and how this pathway can be targeted to normalize the pancreatic phenotype and render it less oncogenic to prevent pancreatic cancer. The following aims are proposed: Aim #1, Determine how the CCK-BR signaling pathway is involved in acinar-ductal metaplasia; Aim #2, Examine how activation of the CCK-B receptor pathway modulates pancreatic stellate cells and if CCK- receptor blockade can change the phenotype to render the fibroblasts less carcinogenic; and Aim #3, Evaluate how activation of the CCK-BR induces tissue inflammation and polarization of immune cells. In this investigation, we will use murine models of pancreatitis in wild-type and in CCK-BR-knockout mice with state of the art techniques as laser microdissection of ADM and stroma, Reverse phase protein array, Mass Cytometry and RNA sequencing to understand plasticity of pancreatic cells. We will also examine the role of the CCK-BR on the pancreatic stellate cells in vitro using murine and human cells. Our goal is to understand how proglumide reprograms a metaplastic or dysplastic pancreas to a more normal phenotype and thus preventing development of pancreatic cancer.

抽象的众所周知，慢性胰腺炎引起的炎症会使患病风险增加 8 倍对于胰腺癌的发展。当细胞受伤或受到压力时，它们可以转变为具有通过称为化生的过程产生不同的表型。在胰腺中，腺泡导管化生 (ADM) 与胰腺炎一起发生，这个过程通常是可逆的。然而，随着慢性炎症或成熟停滞后，导管表型细胞不会逆转其正常腺泡表型，但可能进展为胰腺细胞上皮内瘤变（PanINs）和胰腺癌。我们对机制的理解存在差距参与这种恢复或丧失恢复能力。我们实验室一直在研究G蛋白偶联受体并发现胆囊收缩素-B 受体 (CCK-BR) 存在于导管细胞中，但腺泡细胞中没有在慢性胰腺炎和 PanIN 形成期间表达，并且在胰腺中显着过度表达癌症。使用 CCK 受体拮抗剂丙谷胺治疗可加速 ADM 的恢复，降低炎症，并使胰腺恢复正常表型。在使用 PanIN 或使用 PanIN 的更晚期疾病中胰腺癌，丙谷胺治疗还会改变胰腺细胞外基质或肿瘤通过减少胰腺星状细胞或癌症相关的胶原蛋白产生来改善微环境成纤维细胞并将免疫细胞特征改变为更正常的表型。我们假设 CCK-BR信号通路是胰腺可塑性中一条新颖且关键的通路；压制策略该途径将减少胰腺癌。 Proglumide 已在人类受试者中进行了测试第一阶段临床试验被认为具有广泛的安全性。在本提案中，我们将研究以下角色：丙谷胺和 CCK-BR 在胰腺细胞可塑性中的作用以及如何靶向该途径使胰腺细胞可塑性正常化胰腺表型并降低其致癌性以预防胰腺癌。以下目标是建议：目标#1，确定 CCK-BR 信号通路如何参与腺泡导管化生；目的 #2，检查 CCK-B 受体途径的激活如何调节胰腺星状细胞以及 CCK- 受体阻断可以改变表型，使成纤维细胞的致癌性降低；目标#3，评估 CCK-BR 的激活如何诱导组织炎症和免疫细胞的极化。在本次调查中，我们将使用最先进的野生型和 CCK-BR 敲除小鼠的胰腺炎小鼠模型技术，如 ADM 和基质的激光显微切割、反相蛋白阵列、质谱流式细胞仪和 RNA 测序可了解胰腺细胞的可塑性。我们还将研究 CCK-BR 在使用小鼠和人类细胞在体外培养胰腺星状细胞。我们的目标是了解丙谷胺如何将化生或发育不良的胰腺重新编程为更正常的表型，从而阻止发育胰腺癌。