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.
Highlights
Phenotypic transition of cancer cells induced by chronic metabolic stress (CMS)
CMS-induced cells demonstrated extended viability under metabolic stress, as the medium depleted with glucose after 5–7 days, with 90% cell death being delayed by at least a week compared with parental cells
cancer stem cell (CSC)-rich tumors are associated with aggressive disease and poor prognosis,[5] indicating that an understanding of their biology is pertinent to developing effective therapies
Summary
The tumor metabolic microenvironment, which is continuously reshaped during tumor progression[10,11,12] can influence adaptive cellular behaviors including dormancy, invasion, and metastasis as well as therapy resistance.[13,14,15] Intriguingly, these acquired phenotypes share characteristics with CSClike or TICs.[16,17,18,19] Adaptive behavior of cancer cells in the highly heterogeneous microenvironment[20] is mediated by induction of changes in gene expression thereby reprogramming signaling pathways.[21,22] it was theorized that these emerging adaptive behaviors in cancer might be driven by harsh tumor microenvironmental selective forces.[23]. There are numerous microenvironmental factors that could influence cancer cell behavior, the stem-like characteristics It is well established and widely accepted that the typical triad of tumor microenvironment consists of hypoxia, nutrient depletion and low pH. In response to chronic metabolic stress (CMS), cancer cells acquire and maintain CSC-like characteristics This CSC-like transition is mediated through increased Wnt activity induced by metabolic stress. The Wnt pathway can be exploited by cancer cells to execute a CSC-like phenoconversion that facilitates survival under metabolic stress. These results implicate the Wnt pathway as a critical mediator of CSC-like transition of subclone(s) of tumor cells in response to metabolic stress
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