ABSTRACT
Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.
Subject(s)
Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Diapause , Drug Resistance, Neoplasm , Animals , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Autophagy/genetics , Cell Line, Tumor , Clone Cells , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Embryo, Mammalian/drug effects , Embryo, Mammalian/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Genetic Heterogeneity/drug effects , Humans , Irinotecan/pharmacology , Irinotecan/therapeutic use , Mice, Inbred NOD , Mice, SCID , Models, Biological , Signal Transduction/drug effects , Up-Regulation/drug effects , Up-Regulation/genetics , Xenograft Model Antitumor AssaysABSTRACT
The ability to generate induced pluripotent stem cells from differentiated cell types has enabled researchers to engineer cell states. Although studies have identified molecular networks that reprogram cells to pluripotency, the cellular dynamics of these processes remain poorly understood. Here, by combining cellular barcoding, mathematical modeling, and lineage tracing approaches, we demonstrate that reprogramming dynamics in heterogeneous populations are driven by dominant "elite" clones. Clones arise a priori from a population of poised mouse embryonic fibroblasts derived from Wnt1-expressing cells that may represent a neural crest-derived population. This work highlights the importance of cellular dynamics in fate programming outcomes and uncovers cell competition as a mechanism by which cells with eliteness emerge to occupy and dominate the reprogramming niche.
