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

E. Lee, J. Yang, M. Ku, N. H. Kim, Y. Park, C. B. Park, J. S. Suh, E. S. Park, J. I. Yook, Gordon Mills, Y. M. Huh, J. H. Cheong

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1805
JournalCell Death and Disease
Volume6
DOIs
StatePublished - Jul 2 2015
Externally publishedYes

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Physiological Stress
Neoplastic Stem Cells
Tumor Microenvironment
Wnt Signaling Pathway
Neoplasms
Phenotype
Cellular Microenvironment
Gene Expression Profiling
Transfection
Clone Cells
Maintenance
Neoplasm Metastasis
Food

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Lee, E., Yang, J., Ku, M., Kim, N. H., Park, Y., Park, C. B., ... Cheong, J. H. (2015). Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition. Cell Death and Disease, 6, [e1805]. https://doi.org/10.1038/cddis.2015.171

Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition. / Lee, E.; Yang, J.; Ku, M.; Kim, N. H.; Park, Y.; Park, C. B.; Suh, J. S.; Park, E. S.; Yook, J. I.; Mills, Gordon; Huh, Y. M.; Cheong, J. H.

In: Cell Death and Disease, Vol. 6, e1805, 02.07.2015.

Research output: Contribution to journalArticle

Lee, E, Yang, J, Ku, M, Kim, NH, Park, Y, Park, CB, Suh, JS, Park, ES, Yook, JI, Mills, G, Huh, YM & Cheong, JH 2015, 'Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition', Cell Death and Disease, vol. 6, e1805. https://doi.org/10.1038/cddis.2015.171
Lee, E. ; Yang, J. ; Ku, M. ; Kim, N. H. ; Park, Y. ; Park, C. B. ; Suh, J. S. ; Park, E. S. ; Yook, J. I. ; Mills, Gordon ; Huh, Y. M. ; Cheong, J. H. / Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition. In: Cell Death and Disease. 2015 ; Vol. 6.
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