title: Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition.
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.
authors.affiliation: 1] Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [2] Nanomedical National Core Research Center, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.affiliation: 1] Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [2] Yonsei-KRIBB Medical Convergence Research Institute, Yonsei University Health System, Seoul, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: 1] Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [2] Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: M
authors.initials: M
authors.lastname: Ku
authors.affiliation: Department of Oral pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: N H
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Park
authors.affiliation: Department of Oral pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: C B
authors.initials: CB
authors.lastname: Park
authors.affiliation: 1] Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [2] Yonsei-KRIBB Medical Convergence Research Institute, Yonsei University Health System, Seoul, Korea [3] Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea.
authors.forename: J-S
authors.initials: JS
authors.lastname: Suh
authors.affiliation: Yonsei-KRIBB Medical Convergence Research Institute, Yonsei University Health System, Seoul, Korea.
authors.forename: E S
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Oral pathology, Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea.
authors.forename: J I
authors.initials: JI
authors.lastname: Yook
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: 1] Department of Radiology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [2] Yonsei-KRIBB Medical Convergence Research Institute, Yonsei University Health System, Seoul, Korea [3] Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Huh
authors.affiliation: 1] Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea [2] Department of Surgery, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea [3] Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Cheong
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000473:pathology; D018874:Spheroids, Cellular / Q000473:pathology; D013312:Stress, Physiological / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C555510:WNT3A protein, human; D060509:Wnt3A Protein