Metabolic control of cancer cell stemness: Lessons from iPS cells.

The Nobel prized discovery of nuclear reprogramming is swiftly providing mechanistic evidence of a role for metabolism in the generation of cancer stem cells (CSC). Traditionally, the metabolic demands of tumors have been viewed as drivers of the genetic programming detected in cancer tissues. Beyond the energetic requirements of specific cancer cell states, it is increasingly recognized that metabolism per se controls epi-transcriptional networks to dictate cancer cell fate, i.e., metabolism can define CSC. Here I review the CSC-related metabolic features found in induced pluripotent stem (iPS) cells to provide an easily understandable framework in which the infrastructure and functioning of cellular metabolism might control the efficiency and kinetics of reprogramming in the re-routing of non-CSC to CSC-like cellular states. I suggest exploring how metabolism-dependent regulation of epigenetics can play a role in directing CSC states beyond conventional energetic demands of stage-specific cancer cell states, opening a new dimension of cancer in which the "physiological state" of CSC might be governed not only by cell-autonomous cues but also by local micro-environmental and systemic metabolo-epigenetic interactions. Forthcoming studies should decipher how specific metabolites integrate and mediate the overlap between the CSC-intrinsic "micro-epigenetics" and the "upstream" local and systemic "macro-epigenetics," thus paving the way for targeted epigenetic regulation of CSCs through metabolic modulation including "smart foods" or systemic "metabolic nichotherapies."