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
Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
