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.

Nicotinamide metabolism regulates glioblastoma stem cell maintenance

“…Embryonic stem cells share several metabolic features with cancer to maintain their rapid cell cycles and epigenetic landscape necessary for multilineage potency (13)(14)(15). As with stem cells, tumor cells require concerted dysregulation of metabolism and epigenetic cell states to simultaneously accommodate the bioenergetic demands of increased proliferation and aberrant tumor cell fate through epigenetic modification.…”

The Role of Biomaterials on Cancer Stem Cell Enrichment and Behavior

“…30,31 Acidic pH has also been found to promote an increase of cancer stem cell phenotype. 32 Furthermore, nutrient stress has also been implicated in enhancing cancer stem cell phenotype through Wnt signaling, 33,34 and stromal cells were found to mediate cancer cell adhesion and motility. [35][36][37] Thus, there is a bi-directional effect of the tumor microenvironment in which the environment affects the tumor cell characteristics and in return the tumor cells remodel their microenvironment.…”

Integrated omics-analysis reveals Wnt-mediated NAD+ metabolic reprogramming in cancer stem-like cells

“…We recently reported that chronic metabolic stress induces cancer stem-cell like phenoconversion mediated by Wnt pathway activation [14]. Intriguingly, these CSCs exhibited enhanced survival capability in prolonged glucose starvation conditions, suggesting the acquisition of cellular processes that negate metabolic stress induced cell death [14].…”

“…Intriguingly, these CSCs exhibited enhanced survival capability in prolonged glucose starvation conditions, suggesting the acquisition of cellular processes that negate metabolic stress induced cell death [14]. …”

“…Indeed, CSCs displayed remarkably higher viability than did non-CSCs, which rapidly underwent apoptotic cell death in glucose deprivation [14] (Figure S1). We hypothesized that CSCs could have undergone a metabolic reprogramming associated with anti-apoptotic capability upon chronic metabolic stress arising from glucose deprivation.…”