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

• 批准号: 10187126
• 负责人: Mara H. Sherman
• 金额: $ 43.59万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10187126
• 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

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, IL- 22RA1, 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 IL- 22RA1 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) 目前迫切需要寻找治疗胰腺导管腺癌(PDAC)的新方法。 需要更好地了解发展和复发的潜在机制。慢性炎症 是PDAC的一个特征和独立的危险因素。免疫细胞之间的相互作用，与癌症相关 成纤维细胞(CAF)和癌细胞可促进PDAC的发生和发展。然而，几乎没有什么是 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 识别促进免疫细胞、癌细胞和CAF之间串扰的信号节点，以 促进PDAC的进步。在健康人中，IL-22是由免疫细胞表达的，而其受体IL-22是由免疫细胞表达的。 22Ra1，在非免疫细胞中选择性表达。IL-22和IL-22Ra1的表达均升高 PDAC，但对此信号轴在PDAC中的作用知之甚少。我们最近表现出了高度的， IL-22Ra1在人和小鼠PDAC中的异质性表达重要的是，IL-22Ra1的高表达是 与PDAC患者预后不良有关。此外，我们还发现在PDAC中IL-22RA1高表达细胞 具有癌症干细胞特性，包括体内高致瘤性。我们发现IL-22刺激IL-22 22Ra1通过激活STAT3在PDAC细胞中表达，并假设这个正反馈环 增强PDAC癌细胞的干性和致瘤性。因此，IL-22Ra1/STAT3信号可能提供 高IL-22Ra1治疗PDAC的治疗靶点我们将使用不同的PDAC小鼠模型来研究 腺泡细胞或PSCs中IL-22Ra1基因缺失对PDAC生长、转移和干细胞的影响 在活体内。我们将使用新的多维分析方法来分析炎症是否会导致 IL-22、IL-22在PDAC小鼠模型免疫细胞群中的表达及其致癌作用 用药理学和遗传学方法阻断PDAC中IL-22信号的治疗益处。我们会 检测IL-22/IL-22Ra1轴在人PDAC中的表达及作用。使用原代人胰腺 导管上皮细胞具有明确的PDAC基因驱动突变，我们将研究其贡献和调控 IL-22/IL-22Ra1信号转导通路在人PDAC发育中的作用 我们提出的研究将对遗传驱动因素和炎症如何协调提供新的见解 PDAC中免疫和非免疫成分之间的功能连接和通讯。此外， 我们将从机制上了解(1)免疫细胞、CAF和癌细胞之间的相互作用是如何由 IL-22/IL-22Ra1轴导致PDAC的发生和(2)抑制IL-22/IL-22Ra1信号轴 提供一种针对癌症干细胞的治疗策略，癌症干细胞是治疗阻力的主要因素， 与PDAC相关的预后不良。