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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.

项目总结