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Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition

Authors
 E Lee ; J Yang ; J-H Cheong ; Y-M Huh ; GB Mills ; JI Yook ; ES Park ; J-S Suh ; CB Park ; Y Park ; NH Kim ; M Ku 
Citation
 Cell Death & Disease, Vol.6 : e1805, 2015 
Journal Title
 Cell Death & Disease 
ISSN
 2041-4889 
Issue Date
2015
Abstract
Reciprocal interactions between cancer cells and the tumor microenvironment drive multiple clinically significant behaviors including dormancy, invasion, and metastasis as well as therapy resistance. These microenvironment-dependent phenotypes share typical characteristics with cancer stem cells (CSC). However, it is poorly understood how metabolic stress in the confined tumor microenvironment contributes to the emergence and maintenance of CSC-like phenotypes. Here, we demonstrate that chronic metabolic stress (CMS) in a long-term nutrient deprivation induces a Wnt-dependent phenoconversion of non-stem cancer cells toward stem-like state and this is reflected in the transcriptome analysis. Addition of Wnt3a as well as transfection of dominant-negative Tcf4 establishes an obligatory role for the Wnt pathway in the acquisition of CSC-like characteristics in response to metabolic stress. Furthermore, systematic characterization for multiple single cell-derived clones and negative enrichment of CD44+/ESA+ stem-like cancer cells, all of which recapitulate stem-like cancer characteristics, suggest stochastic adaptation rather than selection of pre-existing subclones. Finally, CMS in the tumor microenvironment can drive a CSC-like phenoconversion of non-stem cancer cells through stochastic state transition dependent on the Wnt pathway. These findings contribute to an understanding of the metabolic stress-driven dynamic transition of non-stem cancer cells to a stem-like state in the tumor metabolic microenvironment.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/140808
DOI
10.1038/cddis.2015.171
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Surgery
1. 연구논문 > 5. Research Institutes > Institute for Medical Convergence
1. 연구논문 > 1. College of Medicine > Yonsei Biomedical Research Center
1. 연구논문 > 1. College of Medicine > Dept. of Radiology
1. 연구논문 > 5. Research Institutes > Oral Cancer Research Institute
1. 연구논문 > 2. College of Dentistry > Dept. of Oral Pathology
Yonsei Authors
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