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

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.

Grant Number: 5K08CA267072-04
NIH Institute/Center: NIH
Principal Investigator: Jason Chan