Definition and perturbation of cell-regulatory heterogeneities in solid tumors

ABSTRACT Cell-state variation in cancer is important for tumor initiation–progression and creates a major hurdle to effective anticancer therapeutics. Unbiased methods are needed to monitor single-cell regulatory states of cancer cells in situ, as are approaches to analyze these data and generate actionable hypotheses about cancer biology. This R50 Research Scientist application will support the activities of Dr. Lixin Wang, a 11-year Research Scientist in the Unit directed by Dr. Kevin Janes, who is an expert in 10-cell transcriptomic profiling by laser-capture microdissection (LCM). Dr. Wang is a co-developer of LCM-based 10-cell RNA sequencing (10cRNA-seq; Sci Rep 2019) and is deeply involved in two NCI-sponsored projects (U01-CA215794 and R01- CA214718) that stem from the technology. As the lead experimentalist for a U01 cooperative agreement through the Cancer Systems Biology Consortium, Dr. Wang will perform molecular-genetic perturbations, epigenomic studies, and in vivo tests of nucleocytoplasmic regulatory states that arise when breast epithelial cells acutely activate the ERBB2 receptor tyrosine kinase. Dr. Wang will support the R01 research project on a heterogeneously regulated tumor-suppressive ligand by training predoctoral students on 3D culture, molecular cloning, intraductal xenografts, and regulatory compliance. In the past, Dr. Wang has collaborated effectively with chemists and mouse geneticists at the University of Virginia (UVA) Cancer Center, all of whom strongly support this R50 application. An R50 award would ensure successful completion of the U01–R01 aims and enable Dr. Wang’s expertise to propagate more broadly within the NCI-supported research activity of the UVA Cancer Center.