To understand the function of subpopulations identified in clinical samples we leverage patient-derived models as well as a collection of >1,000 cell lines. We explore the cellular diversity within hundreds of cell lines and identify the most appropriate model systems. We then use the selected models to isolate particular subpopulations that resemble those found in patients and study their function, including tumor initiation capacity, invasion and drug responses. Finally, genomics and CRISPR-Cas9 technologies are used to reconstruct the regulation of tumor subpopulations and develop novel treatments that would either eradicate those cells or alter their states (differentiation therapy).