Project 2: Immune signals promoting pancreas cancer stemness and progression

项目2：促进胰腺癌干性和进展的免疫信号

基本信息

批准号：
10456770
负责人：
STEVEN E ARTANDI
金额：
$ 41.46万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456770
关键词：
Acinar Cell Affect Cell Communication Cells Chemoresistance Chronic Communication Development Disease Ductal Epithelial Cell Early Diagnosis Environment Epigenetic Process Experimental Models Feedback Fibroblasts Fibrosis Genetic Genetic Engineering Goals Growth Human Immune Immune signaling In Vitro Inflammation Lead Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Mus Neoplasm Metastasis Oncogenic Pancreas Pancreas Transplantation Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Pancreatitis Pathway interactions Patients Peripheral Pharmacology Phenotype Platelet-Derived Growth Factor alpha Receptor Play Population Process Prognosis Property Radiation therapy Recurrence Regulation Resistance Risk Factors Role STAT3 gene Sampling Signal Pathway Signal Transduction Stromal Cells Survival Rate TP53 gene Tamoxifen Testing Therapeutic Tumorigenicity Work acute pancreatitis base cancer cell cancer stem cell cancer subtypes carcinogenesis cell stroma chemotherapy chronic pancreatitis driver mutation genetic approach immunoregulation improved in vivo insight interleukin-22 molecular targeted therapies mouse model novel pancreatic cancer cells pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic stellate cell receptor selective expression single-cell RNA sequencing stemness synergism therapeutic evaluation therapeutic target tissue repair tumor tumor microenvironment tumor progression tumorigenic

项目摘要

ABSTRACT (Project 2) There is an urgent need to discover improved therapies for pancreatic ductal adenocarcinoma (PDAC), which require a better understanding of mechanisms underlying development and recurrence. Chronic inflammation is a feature and an independent risk factor for PDAC. Interactions between immune cells, cancer associated fibroblasts (CAFs), and cancer cells can promote PDAC development and progression. However, little is known about how immune cells or immune cell-related signals affect PDAC development. Our long-term goal is to identify signaling nodes that facilitate the crosstalk between immune cells, cancer cells and CAFs to promote PDAC progression. In healthy subjects, IL-22 is expressed by immune cells while its receptor, IL22RA1, is selectively expressed in non-immune cells. IL-22 and IL-22RA1 expression are both elevated in PDAC, but little is known about the role of this signaling axis in PDAC. We have recently demonstrated high, heterogeneous expression of IL-22RA1 in human and mouse PDAC. Importantly, high IL-22RA1 expression is associated with poor prognosis of PDAC patients. Furthermore, we showed that IL-22RA1high cells in PDAC have cancer stem cell properties, including high tumorigenicity in vivo. We found that IL-22 stimulates IL22RA1 expression through STAT3 activation in PDAC cells, and postulate that this positive feedback loop enhances stemness and tumorigenicity of PDAC cancer cells. Thus, IL-22RA1/STAT3 signaling might provide a therapeutic target to treat PDAC with high IL-22RA1. We will use different mouse models of PDAC to study the effects of genetic deletion of IL-22RA1 in acinar cells or PSCs on PDAC growth, metastasis, and stemness in vivo. We will use novel, multi- dimensional analysis methods to analyze if inflammation drives carcinogenesis via IL-22, IL-22 expression in immune cell populations in PDAC mouse models and test therapeutic benefit of blocking IL-22 signaling in PDAC using pharmacologic and genetic approaches. We will determine the expression and role of IL-22/IL-22RA1 axis in human PDAC. Using primary human pancreatic ductal epithelial cells with defined PDAC genetic driver mutations, we will study the contribution and regulation of IL-22/IL-22RA1 signaling in human PDAC development. Our proposed studies will novel insights into how genetic drivers and inflammation orchestrate functional connection and communication between immune and non-immune components in PDAC. Further, we will gain mechanistic understanding of how (1) immune cell, CAF, and cancer cell interactions mediated by the IL-22/IL-22RA1 axis lead to PDAC development and (2) inhibition of the IL-22/IL-22RA1 signaling axis provides a therapeutic strategy that targets cancer stemness, a major factor in therapy resistance and the dismal prognosis associated with PDAC.

摘要（项目2）迫切需要发现改进的胰腺导管腺癌（PDAC）的疗法，该疗法需要更好地理解发展和复发的基础机制。慢性炎症是PDAC的功能和独立危险因素。免疫细胞之间的相互作用，癌症相关成纤维细胞（CAF）和癌细胞可以促进PDAC的发育和进展。但是，几乎没有了解免疫细胞或免疫细胞相关信号如何影响PDAC的发育。我们的长期目标是确定促进免疫细胞，癌细胞和CAF之间串扰的信号传导节点促进PDAC进展。在健康受试者中，IL-22由免疫细胞表达，而其受体IL 22RA1在非免疫细胞中有选择地表达。 IL-22和IL-22RA1表达均升高 PDAC，但对该信号轴在PDAC中的作用知之甚少。我们最近证明了很高的 IL-22RA1在人和小鼠PDAC中的异质表达。重要的是，高IL-22RA1表达是与PDAC患者的预后不良有关。此外，我们显示了PDAC中的IL-22RA1高细胞具有癌症干细胞特性，包括体内高肿瘤性。我们发现IL-22通过PDAC细胞中的STAT3激活刺激IL 22RA1的表达，并假设这种正反馈循环增强PDAC癌细胞的干性和致瘤性。因此，IL-22RA1/STAT3信号可能会提供用高IL-22RA1治疗PDAC的治疗靶标。我们将使用不同的PDAC鼠标模型来研究 IL-22RA1在腺泡细胞或PSC中的遗传缺失对PDAC生长，转移和干性的影响体内。我们将使用新颖的多维分析方法来分析炎症驱动 PDAC小鼠模型中免疫细胞种群中IL-22，IL-22的癌变和测试使用药理和遗传方法阻止PDAC中IL-22信号传导的治疗益处。我们将确定IL-22/IL-22RA1轴在人PDAC中的表达和作用。使用原发性胰腺具有定义的PDAC遗传驱动突变的导管上皮细胞，我们将研究贡献和调节人类PDAC发育中的IL-22/IL-22RA1信号传导。我们提出的研究将对遗传驱动因素和炎症如何编排进行新的见解 PDAC中免疫和非免疫组件之间的功能连接和通信。更远，我们将对（1）免疫细胞，CAF和癌细胞相互作用如何获得机械理解 IL-22/IL-22RA1轴导致PDAC发育和（2）抑制IL-22/IL-22RA1信号轴提供了针对癌症的治疗策略，这是治疗性耐药性的主要因素与PDAC相关的惨淡预后。