During cancer development, cancer cells grow into multiple genetically related sub-lineages that evolve in parallel and display heterogeneity at multiple levels. This project aims to trace, identify and isolate drug resistant sub-lineages of cancer cell line and PDX models using a cutting-edge DNA barcoding platform developed in the group. By utilizing CRISPR activation, sub-lineages of interest can be isolated in a highly-efficiently manner, which is not feasible with conventional DNA barcoding systems. Isolated cancer sub-lineages can be then biologically characterized using multi-omics profiling to identify key features in drug resistant sub-lineages. The project will improve our understanding of drug-resistant cancer cells and facilitate the development of therapeutic interventions to tackle treatment resistance.