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

确定高可塑性细胞状态在肺腺癌中的作用和功能

基本信息

批准号：
10525396
负责人：
Jason Earl Chan
金额：
$ 24.95万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525396
关键词：
3-Dimensional Ablation Adenocarcinoma Cell Advanced Malignant Neoplasm Advisory Committees American Antineoplastic Agents Area Award Bioinformatics Biology CRISPR/Cas technology Cancer Biology Cancer Etiology Cells Chemoresistance Clinical Complementary DNA Data Development Development Plans Educational workshop Environment Evolution Foundations Funding Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals Histology Human Laboratories Lead Lung Adenocarcinoma Lung Neoplasms Maintenance Malignant Neoplasms Malignant neoplasm of lung Measures Medical Oncologist Medical Oncology Medicine Memorial Sloan-Kettering Cancer Center Mentors Methods Modeling Molecular Molecular Biology Molecular Biology Techniques Molecular Target Pathway interactions Patients Pharmacology Phenotype Physicians Play Proteins Reporter Reproducibility Research Research Personnel Research Project Summaries Resistance Role Scientist Source Stress System Systems Biology Testing Time Training Translating Tumor Burden Tumor stage United States Work allotransplant base cancer cell cancer genetics carcinogenesis career career development chemotherapy experience experimental study human disease improved in vivo in vivo Model inhibitor insight instructor mortality mouse model novel novel strategies novel therapeutics overexpression patient derived xenograft model programs response sarcoma single cell mRNA sequencing single-cell RNA sequencing small hairpin RNA tenure track therapy resistant transcription factor transcriptome transdifferentiation translational cancer research tumor tumor heterogeneity tumor progression vector

项目摘要

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.

项目概要研究：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抵抗。为了了解如何可塑性影响肿瘤，我们分析了基因工程小鼠肺肿瘤的单细胞转录组在各个阶段。我们观察到一组可重复的转录状态，其多样性随着时间的推移而增加。有趣的是，我们鉴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，即增加的潜力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细胞状态的富集。我们在原发性人肺腺癌肿瘤和患者来源的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较差的生存率相关。因此，我们的工作表明高可塑性细胞状态驱动肿瘤进展和肺部治疗耐药腺癌。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功能抗性和ii)定义控制高可塑性细胞状态的转录驱动因素。这项工作将提供高可塑性细胞状态的功能和分子定义，将为肺病提供新疗法腺癌。候选人和环境：Jason E. Chan 博士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教授医师科学家研究肿瘤可塑性和肿瘤进化。他制定了一个5年的职业计划，该计划建立在他的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肿瘤内科培训。该项目将为陈博士提供使用最先进技术的理想培训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来剖析其作用致癌过程中的高可塑性细胞状态。陈博士将由 Tuomas Tammela 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作业、研讨会、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，并具有支持性研究经验 MSKCC 的学术机构环境是转化癌症研究的卓越中心。该项目的成功完成将带来治疗患者的新方法，并将提供为陈博士成为独立研究者奠定了基础，并拥有自己的 R01 资助实验室。