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.
Bibliographical noteFunding Information:
Acknowledgements. This work was supported by NCI 5 P01CA0099031, Stand Up to Cancer/American Association for Cancer Research Dream Team Translational Cancer Research Grant No. SU2C-AACR-DT0209, Susan G Komen Breast Cancer Foundation Grant KG08169404 and CCSG grant P30 CA016672 (to GBM), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP; NRF-2011-0030086), and the National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (1020390 and 1220100).
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience
- Cell Biology
- Cancer Research