Dissecting the role of Notch signaling in the pancreatic cancer microenvironment.

剖析 Notch 信号在胰腺癌微环境中的作用。

• 批准号: 10464043
• 负责人: Filip Bednar
• 金额: $ 52.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464043
• 关键词: Apoptosis; Biological Assay; Cause of Death; Cell physiology; Cells; Coculture Techniques; Combination immunotherapy; Complex; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease model; Embryo; Epithelial; Epithelial Cells; Erinaceidae; Fibroblasts; Genes; Genetic; Genetic Engineering; Genetically Engineered Mouse; Goals; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunosuppression; Immunotherapy; In Vitro; Lead; Ligands; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Modeling; Mus; Myelogenous; Myeloid Cells; Nature; Organoids; Pancreas; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Regulatory Pathway; Role; Sampling; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Transplantation; Tumor Cell Line; Tumor-associated macrophages; United States; Work; base; cancer initiation; cell type; checkpoint inhibition; chemotherapy; early phase clinical trial; exhaust; experimental study; gamma secretase; immune checkpoint blockade; immunomodulatory therapies; in vivo; inhibitor; innovation; macrophage; mouse model; notch protein; novel; novel strategies; pancreatic cancer model; pancreatic neoplasm; polarized cell; pre-clinical; therapy resistant; transplant model; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary/Abstract Pancreatic cancer is marked by an immunosuppressive tumor microenvironment contributing to the overall therapeutic resistance seen in this deadly malignancy. Although Notch signaling is integral in the progression of pancreatic neoplasia, its role in the establishment and maintenance of the immunosuppressive tumor microenvironment is unclear. The long-term goal is to define the role of intercellular signaling pathways like Notch in the treatment resistance in pancreatic cancer. The overall objective of this application is to define how Notch regulates myeloid and, as a consequence, T cell polarization in the pancreatic tumor microenvironment to regulate its immunosuppressive nature. The central hypothesis of the application is that Notch serves as one of the key regulatory pathways promoting the establishment of immunosuppressive myeloid and exhausted or anergic T cell populations. The rationale for this proposal is that understanding the mechanistic basis and effects of Notch signaling on the pancreatic tumor microenvironment will identify new approaches to sensitize pancreatic cancer to existing therapies including immunotherapy. The central hypothesis will be tested through three specific aims – 1. Dissect Notch signaling in the pancreatic cancer microenvironment; 2. Define the mechanism and direct effects of Notch signaling on myeloid polarization and function; 2. Target Notch signaling to alleviate immune suppression in pancreatic cancer. We will use a combination of human and mouse pancreatic cancer samples, genetically engineered mouse models, orthotopic tumor models, and human and murine tumor cell lines will be used. In addition, we will use human organoids and cancer associated fibroblasts, together with patient-matched immune cells. Notch signaling will be disrupted via genetic and pharmacologic approaches both in vivo and in vitro to define its role in myeloid compartment function. The proposed work is innovative because it defines novel roles of Notch signaling in pancreatic cancer outside its known epithelial function. It is significant because it allows for the potential development of new immunomodulatory treatments for this deadly disease.

项目总结/摘要 胰腺癌的标志是免疫抑制性肿瘤微环境，其有助于整体免疫抑制。 在这种致命的恶性肿瘤中发现了治疗抗性。尽管Notch信号传导在肿瘤的进展中是不可或缺的， 胰腺肿瘤，其在免疫抑制肿瘤的建立和维持中的作用 微环境不清楚。长期目标是确定像Notch这样的细胞间信号通路的作用 在胰腺癌的治疗耐药性中。本应用程序的总体目标是定义Notch如何 调节胰腺肿瘤微环境中的髓样细胞，并因此调节T细胞极化， 调节其免疫抑制性质。该应用程序的中心假设是，Notch作为 促进免疫抑制性髓系细胞建立的关键调节途径， 无反应性T细胞群。这一建议的基本原理是，了解机械基础和影响 Notch信号在胰腺肿瘤微环境中的作用将确定新的方法来敏化胰腺癌。 癌症与现有疗法，包括免疫疗法。 中心假设将通过三个具体目标进行检验- 1.剖析胰腺癌微环境中的Notch信号传导; 2.明确Notch信号对骨髓极化和功能的机制和直接影响; 2.靶向Notch信号传导以减轻胰腺癌中的免疫抑制。 我们将使用人类和小鼠胰腺癌样本的组合，基因工程小鼠 模型、原位肿瘤模型以及人和鼠肿瘤细胞系。此外，我们将使用 人类器官和癌症相关的成纤维细胞，以及患者匹配的免疫细胞。凹口 将通过体内和体外的遗传和药理学方法破坏信号传导，以确定其作用 在骨髓间室功能方面。拟议的工作是创新的，因为它定义了新颖的角色缺口 在胰腺癌已知的上皮功能之外的信号传导。 这是重要的，因为它允许潜在的开发新的免疫调节治疗， 致命的疾病