Modeling and characterizing early ALK-dependent lung tumorigenesis

PROJECT SUMMARY Lung cancer in never-smokers comprises up to a quarter of lung adenocarcinomas. One of the most frequent subtypes of LCINS is caused by chromosomal rearrangements leading to activation of Anaplastic Lymphoma Kinase (ALK). Early detection of ALK+ cancer is not possible, and it is usually diagnosed at the metastatic stage. This proposal combines several unique and complementary resources and approaches, including patient samples, primary stem cell cultures, mouse modeling, and single cell technologies, to address the critical need to identify and understand the early cellular and molecular changes that occur upon ALK activation. Aim 1 will develop a single cell atlas of ALK+ lung cancer by profiling patient samples and examine the effect of ALK on plasticity in engineered lung organoids. Aim 2 will test the functional relevance of the redox-buffering transcription factor NRF2 in ALK+ lung cancer initiation. Together the aims presented in this proposal will provide the first molecular characterization of early ALK+ lung cancer and provide a foundation for the development of novel diagnostic and therapeutic strategies for this devastating disease. Dr. Peggy Hsu, MD, PhD is a physician-scientist performing mentored research in the laboratory of Dr. Jason Spence and is co-mentored by Dr. Sofia Merajver. Her long-term goal is to be an extramurally funded research program that aims to understand the principles of cell fate determination and its dysregulation in lung cancer. During the K08 training period, Dr. Hsu will acquire additional scientific training and develop skills required for managing an independent laboratory. She will spend at least 75% of her time engaged in the proposed research with the rest of her effort spent taking care of patients with cancer. Dr. Spence is an expert in lung developmental biology and organoid modeling, Dr. Merajver is a leader in translational oncology, and Dr. Hsu will be guided by an exceptional Scientific Advisory and Career Development committee. With an exemplary institutional environment and commitment, training plan, program, mentorship, and proposed research, this K08 award will enable Dr. Hsu to conduct groundbreaking research and transition to independence.