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

项目总结/摘要 胰腺癌仍然是最致命的癌症之一，预期5年生存率<5%。 每年有超过45，000例新诊断和类似的死亡人数使其成为第四大 在美国癌症相关死亡的常见原因。尽管在乳腺癌方面取得了重大进展， 结肠癌和黑色素瘤，胰腺癌的死亡率没有明显的变化， 过去四十年使胰腺癌特别难以治疗的两个因素是其相对的 倾向于早期传播和对化疗和放疗的抵抗。一个提议的 这两种现象的基础机制是上皮向间质转化（EMT），其中 胰腺导管细胞获得了脱落其极性和粘附蛋白的能力， 周围基质进入血管和毛细血管。我们发现细胞因子水平升高 白细胞介素-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 调节EMT的基因转录。我们还发现，IL-22促进肿瘤细胞的侵袭和增殖， 胰腺肿瘤细胞，体外，和肿瘤移植和生长，体内。在本提案中，我们将确定 IL-22如何导致胰腺癌细胞中的EMT，并更好地确定其在癌症发生中的意义， 进展，体内。我们还将探讨先天性淋巴细胞作为IL-22肿瘤内来源的作用 在老鼠和人类身上都是如此。 这个应用程序的总体目标是支持我继续培训和发展，成为一个 肿瘤免疫学和胰腺癌生物学的独立研究者。职业发展计划是 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 我得到了我的部门的慷慨支持和保护时间，并将与我的导师博士密切合作。 Weiping Zou，MD，PhD，一位受人尊敬和经验丰富的肿瘤免疫学家。我还建立了一个 导师委员会，每个人都有免疫学和/或胰腺癌生物学方面的专业知识， 作为一名研究人员，我的任务是促进我的发展，并帮助完成这个项目。我的主要研究 目的是确定IL-22导致EMT的机制，并确定其在EMT中的生物学意义。 原位胰腺癌小鼠模型。本文的主要研究内容体现了我的研究兴趣 在本提案的具体目的中：（1）确定胰腺细胞中的IL-22信号传导如何导致EMT，（2） 为了确定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，和（3）确定主要来源 IL-22在人类和小鼠胰腺肿瘤中的作用。 这些研究的成功完成应该会增加我们对先天性炎症的作用的理解， 胰腺癌的发生和发展，并为这种难以治疗的疾病提供新的免疫靶点。 恶性肿瘤

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.