Role of Interleukin-22 and Innate Lymphoid Cells in Pancreas Cancer Initiation and Progression

Interleukin-22 和先天淋巴细胞在胰腺癌发生和进展中的作用

基本信息

批准号：
9313852
负责人：
Timothy Louis Frankel
金额：
$ 10.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313852
关键词：
Active Learning Adhesives Antibodies Basic Science Benign Biological Assay Biological Response Modifiers Blood Vessels Cancer Biology Cancer Etiology Carcinoma Cells Cessation of life Chronic Colon Carcinoma Cytokine Activation Cytokine Signaling DNA Sequence Alteration Data Development Development Plans Diagnosis Disease Doctor of Philosophy Ductal Epithelial Cell Elements Engraftment Epithelial Cells Event Excision Gastrointestinal tract structure Genetic Transcription Genetically Engineered Mouse Goals Growth Host Defense Human Immune Immunologist Immunology Immunotherapeutic agent In Vitro Inflammation Invaded Knowledge Lead Lesion Link Lymphatic Lymphoid Cell Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mentors Mentorship Methods Modeling Mus NF-kappa B Neoplasm Metastasis Operative Surgical Procedures Organ Pancreas Pancreatectomy Pancreatic Adenocarcinoma Pancreatic duct Pancreatitis Pathway interactions Patients Pharmacology Phenotype Play Population Positioning Attribute Premalignant Proteins Publishing Radiation Recombinant Interleukins Regulation Research Research Personnel Resistance Risk Role STAT3 gene Signal Transduction Site Source Specimen Staining method Stains T-Lymphocyte Time Tissues Training Transgenic Organisms Tumorigenicity United States Work acute pancreatitis base cancer initiation cancer invasiveness career development chemotherapy chronic pancreatitis cytokine epithelial to mesenchymal transition experience in vivo interest interleukin-22 malignant breast neoplasm melanoma member mortality mouse model new therapeutic target pancreatic cancer cells pancreatic neoplasm receptor repaired tissue repair transcription factor tumor tumor immunology tumor initiation tumor progression tumorigenic

项目摘要

Project Summary/Abstract Pancreas adenocarcinoma remains among the most lethal cancers with an expected 5-year survival of <5%. There are over to 45,000 new diagnoses each year and a similar number of deaths making it the fourth most common cause of cancer related mortality in the United States. Despite significant progress in breast cancer, colon cancer and melanoma, there has been no appreciable change in the mortality from pancreas cancer in the past four decades. Two factors that make pancreas cancer particularly difficult to treat are its relative proclivity towards early dissemination and its resistance to chemotherapy and radiation. One proposed mechanism that underlies both of these phenomena is epithelial to mesenchymal transition (EMT) in which pancreatic ductal cells gain the ability to shed their polarity and adhesive proteins and invade through surrounding stroma into blood vessels and lymphatics. We have identified elevated levels of the cytokine interleukin-22 (IL-22) in pre-invasive and invasive pancreas cancers and demonstrated its ability to increase transcription of genes that mediate EMT. We have also shown that IL-22 promotes invasion and proliferation of pancreatic tumor cells, in-vitro, and tumor engraftment and growth, in-vivo. In this proposal, we will determine how IL-22 leads to EMT in pancreas cancer cells and better determine its significance in cancer initiation and progression, in-vivo. We will also explore the role of innate lymphoid cells as the intra-tumoral source of IL-22 both in mice and humans. The overall goal of this application is to support my continued training and development to become an independent investigator in tumor immunology and pancreas cancer biology. The career development plan is based on formal didactic coursework, experiential learning and mentored basic science training. I have received generous support and protected time from my department and will work closely with my mentor Dr. Weiping Zou, MD, PhD, a respected and experienced tumor immunologist. I have also constructed a mentorship committee, each of whom has expertise in immunology and/or pancreas cancer biology and is tasked with furthering my development as a researcher and helping complete this project. My main research goals are to determine the mechanisms by which IL-22 leads to EMT and determine its biologic significance in an autochthonous pancreas cancer murine model. The major themes of the my research interests are reflected in the Specific Aims of this proposal: (1) To determine how IL-22 signaling in pancreas cells leads to EMT, (2) to determine the effect of IL-22 signaling on pancreas cancer initiation, progression and metastasis in a genetically engineered mouse model of pancreas adenocarcinoma, and (3) to identify the predominant source of IL-22 in pancreas tumors in both humans and mice. Successful completion of these studies should increase our understanding of the role of innate inflammation in pancreas cancer initiation and progression and provide new immunotherapeutic targets for this difficult to treat malignancy.

项目概要/摘要胰腺癌仍然是最致命的癌症之一，预计 5 年生存率 <5%。每年有超过 45,000 例新确诊病例和类似的死亡人数，使其成为第四大病例在美国，癌症相关死亡的常见原因。尽管乳腺癌治疗取得了重大进展，与结肠癌和黑色素瘤相比，胰腺癌的死亡率没有明显变化过去的四十年。使胰腺癌特别难以治疗的两个因素是其相对的早期传播的倾向及其对化疗和放疗的抵抗力。一项提议这两种现象背后的机制是上皮间质转化（EMT），其中胰腺导管细胞获得脱落其极性和粘附蛋白并侵入的能力周围基质进入血管和淋巴管。我们发现细胞因子水平升高白介素 22 (IL-22) 在浸润前和浸润性胰腺癌中的作用，并证明其能够增加介导 EMT 的基因转录。我们还发现 IL-22 可以促进细胞的侵袭和增殖。胰腺肿瘤细胞，体外，以及肿瘤体内移植和生长。在本提案中，我们将确定 IL-22 如何导致胰腺癌细胞发生 EMT，并更好地确定其在癌症发生和发展中的重要性进展，体内。我们还将探讨先天淋巴细胞作为 IL-22 肿瘤内来源的作用无论是在小鼠还是人类中。该应用程序的总体目标是支持我的持续培训和发展，成为一名肿瘤免疫学和胰腺癌生物学的独立研究者。职业发展规划是基于正式的教学课程、体验式学习和指导的基础科学培训。我有得到了我所在部门的慷慨支持和受保护的时间，并将与我的导师 Dr. 邹卫平，MD，PhD，一位受人尊敬且经验丰富的肿瘤免疫学家。我还构建了一个导师委员会，每个人都拥有免疫学和/或胰腺癌生物学方面的专业知识，并且是任务是促进我作为一名研究人员的发展并帮助完成这个项目。我的主要研究目标是确定 IL-22 导致 EMT 的机制并确定其在一种本地胰腺癌小鼠模型。反映了我的研究兴趣的主要主题该提案的具体目标是：(1) 确定胰腺细胞中的 IL-22 信号传导如何导致 EMT，(2) 确定 IL-22 信号传导对胰腺癌发生、进展和转移的影响胰腺癌的基因工程小鼠模型，以及（3）确定主要来源 IL-22 在人类和小鼠胰腺肿瘤中的表达。这些研究的成功完成应该会增加我们对先天性炎症在疾病中的作用的理解。胰腺癌的发生和进展，并为这种难以治疗的疾病提供新的免疫治疗靶点恶性肿瘤。