Determining the role and function of a high plasticity cell state in lung adenocarcinoma

项目摘要 研究：肺癌仍然是美国最致命的癌症之一，部分原因是肿瘤 可塑性驱动肿瘤内异质性并导致治疗抗性。为了理解如何 可塑性影响肿瘤，我们分析了来自基因工程小鼠肺肿瘤的单细胞转录组， 在不同的阶段。我们观察到一组可重复的转录状态，其多样性随时间增加。 有趣的是，我们确定并转录定义了每个肿瘤中出现的高可塑性细胞状态。我们 分析了这种细胞状态，并确定了表型转换的强大潜力， 在肿瘤球培养物中的球状体形成，增加的增殖潜力和肿瘤形成能力， 同种异体移植模型，以及体内化疗应激后这种可塑性细胞状态的富集。我们 在原发性人肺腺癌肿瘤和患者源性肺腺癌肿瘤中发现了类似的可塑性细胞状态， 异种移植模型，我们发现细胞状态与患者的生存率更差相关。因此，我们的工作 表明高可塑性细胞状态驱动肿瘤进展和对肺中治疗的抗性 腺癌为了更好地理解高可塑性细胞状态的功能作用，我建议i） 探讨高可塑性细胞状态在肺腺癌进展和治疗中的作用 ii）定义控制高可塑性细胞状态的转录驱动因子。这项工作将提供 高可塑性细胞状态的功能和分子定义，这将为肺部疾病提供新的治疗方法。 腺癌 候选人与环境：Jason E. Chan是纪念医院医学系的讲师 斯隆凯特琳癌症中心（MSKCC）。他的目标是成为一名独立的终身制物理学家兼科学家 研究肿瘤可塑性和肿瘤进化。他描绘了一个5年的职业规划， 生物信息学和系统生物学，遗传学，小鼠模型，分子生物学和临床背景 接受肿瘤内科学培训。这个项目将为陈博士提供理想的培训，以使用最先进的技术 基因组学和分子生物学技术，小鼠模型和患者来源的异种移植物，以剖析作用 癌发生过程中高可塑性细胞的状态。陈博士将由Tuomas塔梅拉博士共同指导 以及MSKCC癌症生物学和遗传学项目的Scott Lowe博士。候选人的职业生涯 发展计划包括课程、讲习班、跨学科咨询委员会的指导 由杰出的基础科学家和医学肿瘤学家组成，并在支持 MSKCC的学术机构环境，一个卓越的转化癌症研究中心。 该项目的成功完成将导致治疗患者的新方法，并将提供一个 基金会为陈博士成为一个独立的研究者与他自己的R01资助的实验室。

PROJECT SUMMARY RESEARCH: Lung cancer remains one of the deadliest cancers in the United States, in part due to tumor plasticity that drives intratumoral heterogeneity and leads to therapy resistance. In order to understand how plasticity impacts tumors, we profiled single cell transcriptomes from genetically engineered mouse lung tumors at various stages. We observed a set of reproducible transcriptional states whose diversity increased over time. Interestingly, we identified and transcriptionally defined a high plasticity cell state that arose in every tumor. We profiled this cell state and identified a robust potential for phenotypic switching, an increased potential for spheroid formation in tumor sphere cultures, an increased proliferative potential and tumor forming ability in allotransplant models, and an enrichment of this plastic cell state after chemotherapeutic stress in vivo. We identified a similar plastic cell state in both primary human lung adenocarcinoma tumors and patient-derived xenograft models, and we found the cell state to be associated with worse survival for patients. Thus, our work suggests that the high plasticity cell state drives tumor progression and resistance to therapy in lung adenocarcinoma. To better understand the functional role of the high plasticity cell state, I propose to i) interrogate the function of the high plasticity cell state in lung adenocarcinoma progression and treatment resistance and ii) define the transcriptional drivers controlling the high plasticity cell state. This work will provide a functional and molecular definition of the high plasticity cell state, which will provide new therapies for lung adenocarcinoma. CANDIDATE & ENVIRONMENT: Dr. Jason E. Chan is an Instructor in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSKCC). His goal is to become an independent tenure-track physician-scientist investigating tumor plasticity and tumor evolution. He has delineated a 5-year career plan that builds upon his background in bioinformatics and systems biology, genetics, mouse models, molecular biology, and clinical training in medical oncology. This project will provide the ideal training for Dr. Chan to use state of the art genomics and molecular biology techniques, mouse models, and patient-derived xenografts to dissect the role of the high plasticity cell state during carcinogenesis. Dr. Chan will be co-mentored by Dr. Tuomas Tammela and Dr. Scott Lowe of the Cancer Biology and Genetics Program at MSKCC. The candidate’s career development plan includes coursework, workshops, mentoring from an interdisciplinary advisory committee comprising of distinguished basic scientists and medical oncologists, and research experience in the supportive academic institutional environment of MSKCC, a center of excellence in translational cancer research. Successful completion of the project will lead to new approaches for treating patients and will provide a foundation for Dr. Chan to become an independent investigator with his own R01 funded laboratory.