The Role of CD4+ T Cells in Oncogene Addiction

项目描述（申请人提供）：Stephanie C.凯西在斯坦福大学医学系肿瘤学系的赞助商迪安费尔舍博士。该项目将有助于了解免疫系统如何促进癌基因引起的肿瘤。Felsher实验室研究癌基因如何启动和维持肿瘤发生。癌基因是当突变时具有将正常细胞转变为癌细胞的潜力的基因。我们的实验室利用Tet-system生成转基因小鼠模型，以调节选择基因的表达，例如癌基因MYC（人类癌症中最常见的失调基因之一），以及其他癌基因，如RAS，BCR-ABL和BCL 2，无论是独立还是合作。我们已经发现癌基因失活导致肿瘤显著消退，并且我们已经表明，一个功能正常的免疫系统对于诱发癌基因成瘾是必不可少的。在拟议的培训期间，该项目将阐明CD 4 + T细胞（Felsher实验室先前证明的对持续肿瘤消退至关重要的免疫细胞）如何对肿瘤微环境做出贡献。该项目将测试这些CD 4 + T细胞是否表达抗血管生成的血小板反应蛋白-1（TSP-1），是否有助于衰老的发展，以及是否招募B细胞以产生抗肿瘤记忆。Felsher实验室的专门转基因小鼠工具允许在肿瘤微环境中检查癌基因信号传导的特殊方法。该项目的预期成果是增加对适应性免疫系统的部分如何与癌基因一起靶向治疗癌症的理解。未来的实验可能会验证我们在人类患者中的结果。这项工作的影响可能对新的“可药物化”治疗靶点产生影响，并将有助于开发新的癌症治疗方法。这项研究将有助于拓宽目前对免疫系统如何促进肿瘤生长和肿瘤消退的理解。此外，这项研究的结果可能会提供关于TSP-1作为抗癌疗法的潜在用途的见解。申请人积极性很高，目标是作为癌症生物学领域的独立研究者从事学术研究事业。申请人设计了特定的实验，以使用新型转基因小鼠模型测试靶向假设。将使用小鼠模型、原代细胞和细胞系培养、流式细胞术和细胞分选、基因和蛋白质表达研究、多参数成像模式和体外研究等技术。!

DESCRIPTION (provided by applicant): A postdoctoral project is proposed by Stephanie C. Casey at the Department of Medicine, Division of Oncology at Stanford University under the sponsor Dr. Dean Felsher. This project will help understand how the immune system contributes to tumors caused by oncogenes. The Felsher laboratory studies how oncogenes initiate and maintain tumorigenesis. Oncogenes are genes that, when mutated, have the potential to turn a normal cell into a cancerous cell. Our laboratory utilizes the Tet-system to generate transgenic mouse models to modulate expression of select genes, such as the oncogene MYC (one of the most commonly dysregulated genes in human cancer), as well as other oncogenes such as RAS, BCR-ABL, and BCL2, both independently and cooperatively. We have found oncogene inactivation elicits dramatic tumor regression, and we have shown that a functioning immune system is essential to elicit oncogene addiction. During the proposed training, this project will elucidate how CD4+ T cells, an immune cell previously demonstrated by the Felsher laboratory to be crucial for sustained tumor regression, contribute to the tumor microenvironment. The project will test whether these CD4+ T cells express anti-angiogenic Thrombospondin-1 (TSP-1), assist in the development of senescence, and recruit B cells to generate anti-tumor memory. The Felsher lab's specialized transgenic mouse tools allow for an exceptional approach to examine oncogene signaling in the context of tumor microenvironment. The anticipated outcome of this project is an increased understanding of how parts of the adaptive immune system may be targeted alongside oncogenes to treat cancer. Future experiments may validate our results in human patients. The impact of this work may have implications for novel "druggable" therapeutic targets and will assist in the development of new cancer treatments. This research will help broaden the current understanding of how the immune system contributes to tumor growth and tumor regression. Furthermore, the findings from this study may provide insight as to the potential use of TSP-1 as an anti-cancer therapy. The applicant is highly motivated and aims to pursue an academic research career as an independent investigator in the field of cancer biology. The applicant has designed specific experiments to test targeted hypotheses using novel transgenic mouse models. Techniques such as mouse models, culture of primary cells and cell lines, flow cytometry and cell sorting, gene and protein expression studies, multi-parameter imaging modalities, and in vitro studies will be used. !