The Role of CD4+ T Cells in Oncogene Addiction

描述(由申请人提供)：斯坦福大学肿瘤学分部医学系的斯蒂芬妮·C·凯西在发起人迪恩·费尔舍博士的指导下，提出了一个博士后项目。这个项目将有助于理解免疫系统如何导致由癌基因引起的肿瘤。费尔谢尔实验室研究癌基因如何启动和维持肿瘤的形成。癌基因是一种基因，当发生突变时，有可能将正常细胞转变为癌细胞。我们的实验室利用Tet系统产生转基因小鼠模型，以独立和协同地调节选定基因的表达，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bcl2。我们发现癌基因失活会导致肿瘤急剧消退，而且我们已经证明，正常运作的免疫系统对于引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CD4+T细胞是如何为肿瘤微环境做出贡献的。该项目将测试这些CD4+T细胞是否表达抗血管生成血栓反应蛋白-1(TSP-1)，帮助衰老的发展，并招募B细胞来产生抗肿瘤记忆。费尔谢尔实验室专门的转基因小鼠工具允许在肿瘤微环境的背景下使用一种特殊的方法来检查癌基因信号。该项目的预期结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。未来的实验可能会在人类患者身上验证我们的结果。这项工作的影响可能会对新的“可用药”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，这项研究的发现可能为TSP-1作为抗癌治疗的潜在用途提供洞察力。申请者有很高的积极性，目标是在癌症生物学领域从事学术研究生涯，成为一名独立的调查员。申请者设计了具体的实验，使用新的转基因小鼠模型来测试有针对性的假设。将使用小鼠模型、原代细胞和细胞系的培养、流式细胞术和细胞分选、基因和蛋白质表达研究、多参数成像方式和体外研究等技术。好了！

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. !