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

 E Lee  ;  J Yang  ;  M Ku  ;  NH Kim  ;  Y Park  ;  CB Park  ;  J-S Suh  ;  ES Park  ;  JI Yook  ;  GB Mills  ;  Y-M Huh  ;  J-H Cheong 
 CELL DEATH & DISEASE, Vol.6 : 1805, 2015 
Journal Title
Issue Date
Animals ; Breast Neoplasms/pathology* ; Cell Proliferation ; Cell Survival ; Female ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplastic Stem Cells/cytology* ; Neoplastic Stem Cells/pathology ; Spheroids, Cellular/pathology ; Stress, Physiological/physiology* ; Transcription, Genetic/genetics ; Transcriptional Activation/genetics ; Tumor Cells, Cultured ; Tumor Microenvironment/physiology ; Wnt Signaling Pathway/physiology* ; Wnt3A Protein/metabolism* ; Xenograft Model Antitumor Assays
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.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Institute for Medical Convergence (연의-생공연 메디컬융합연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Oral Cancer Research Institute (구강종양연구소) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Ku, Min Hee(구민희) ORCID logo https://orcid.org/0000-0002-1674-1474
Kim, Nam Hee(김남희) ORCID logo https://orcid.org/0000-0002-3087-5276
Park, Eun Sung(박은성)
Suh, Jin Suck(서진석) ORCID logo https://orcid.org/0000-0001-9455-9240
Yang, Jae Moon(양재문) ORCID logo https://orcid.org/0000-0001-7365-0395
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
Lee, Eu Gene(이유진)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Huh, Yong Min(허용민) ORCID logo https://orcid.org/0000-0002-9831-4475
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