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

项目摘要/摘要 胰腺癌仍然是最致命的癌症之一，预计5年生存率为5%。 每年有超过45000例新诊断和类似数量的死亡，使其成为全球第四大 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，胰腺癌死亡率在#年没有明显变化。 在过去的四十年里。使胰腺癌特别难治疗的两个因素是它的相关因素 早期传播的倾向及其对化疗和放射的抵抗力。一项建议 导致这两种现象的机制是上皮向间充质转化(EMT) 胰腺导管细胞获得了脱落其极性和黏附蛋白并通过 周围的间质进入血管和淋巴管。我们已经确认细胞因子水平升高 白细胞介素22(IL-22)在胰腺癌前病变和侵袭性胰腺癌中的表达及其升高能力 调节EMT的基因转录。我们还表明，IL-22促进了肿瘤的侵袭和增殖 胰腺肿瘤细胞，体外，肿瘤植入和生长，体内。在这份提案中，我们将确定 IL-22如何在胰腺癌细胞中诱导EMT并更好地确定其在肿瘤发生和发展中的意义 进展，在体内。我们还将探讨先天淋巴样细胞作为IL-22的肿瘤内来源的作用 无论是在老鼠身上还是在人类身上。 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名 肿瘤免疫学和胰腺癌生物学的独立研究员。职业发展计划是 基于正规授课、体验式学习和辅导式基础科学培训。我有过 从我的部门得到了慷慨的支持和保护，并将与我的导师Dr。 邹卫平，医学博士，受人尊敬和经验丰富的肿瘤免疫学家。我还构建了一个 导师委员会，每个人都有免疫学和/或胰腺癌生物学方面的专业知识，并且 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，并确定其生物学意义。 一种自体胰腺癌小鼠模型。反映了我的研究兴趣的主要主题 在这项提案的具体目标中：(1)确定胰腺细胞中IL-22信号如何导致EMT，(2) 探讨IL-22信号在胰腺癌发生、发展和转移中的作用。 基因工程小鼠胰腺癌模型的建立，以及(3)确定主要来源 IL-22在人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炎症在 胰腺癌的发生发展及其免疫治疗的新靶点 恶毒。

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.