The mechanism and function of cell competition in tumors

我的长期职业目标是获得终身教职，并在癌细胞生物学领域建立一个独立的研究项目。我提出了一个三年的职业发展计划，使我成为一名成功的独立研究调查员。在本研究中，我将重点了解肿瘤中细胞竞争的机制和功能，实现三个具体目标：(1)确定NF2突变肿瘤细胞中YAP的差异表达是否可以诱导细胞竞争；(2)鉴定YAP差异表达诱导克隆优势过程中的介导因子；(3)确定不同表达YAP的肿瘤细胞间相互作用对肿瘤发生的影响。本研究的主要方法将是肿瘤细胞克隆优势模型。本研究的结果将提供肿瘤细胞间竞争性相互作用的机制和功能指示。此外，由于细胞竞争可以调节肿瘤的进展和治疗反应，鉴定出的竞争性相互作用的分子介质和效应物可能发展成为诊断标志物或治疗靶点。我提出的职业发展规划是基于我过去独特的科学经历，这使我成为攻读这一学科的理想人选。由于该项目处于开发的早期阶段，预计管理拟议工作的高风险方面，例如建立模型和研究工具，在技术上具有挑战性。在争取K22奖项的过程中，我的目标是获得更多的蜂窝研究技能

DESCRIPTION (provided by applicant): My long-term career goal is to secure a tenure-track faculty position and establish an independent research program in the area of cancer cell biology. I propose a three-year career development plan that will enable me to become a successful independent research investigator. In this proposed research, I will focus on understanding the mechanism and function of cell competition in tumors by achieving three specific aims: (1) to determine if differential YAP expression in NF2 mutant tumor cells can induce cell competition; (2) to identify mediators in the clonal dominance process induced by differential YAP expression; and (3) to determine the impact of the interaction between tumor cells differentially expressing YAP on tumorigenesis. The main approach in this study will be tumor cell clonal dominance models. Results from this proposed research will provide mechanistic and functional indications of the competitive interaction between tumor cells. Moreover, identified molecular mediators and effectors of the competitive interaction might be developed into diagnostic markers or therapeutic targets since cell competition could modulate tumor progression and therapeutic response. This proposed career development plan is based on my past unique scientific history, which makes me an ideal person to pursue this subject. Because this project is in the early stages of development, management of high risk aspects of the proposed work, such as establishment of models and research tools, is anticipated to be technique-challenging. In seeking a K22 award, I aim to gain additional skills in studying cellular interactions in cancer. These skills will be obtained through attending courses and consulting/collaborating with related experts. Dr. Filippo Giancotti's lab, a well-known research program in studying cell adhesion and signaling in cancer biology, as well as MSKCC, an ideal environment with state-of- the-art core facilities and a highly interactive scientific community, provide me unique recourses for my research and other career development activities to strengthen my professional skills in: grant and manuscript writing, presentation, the application process and negotiations for tenure track positions, mentoring and lab management. The K22 award would provide me with protected time critical to strengthen the new research subject and would foster my interaction with the diverse expertise in this community, facilitate my maturation as an independent researcher, and enable a smooth transition toward my independent career.