Metabolomic mapping of cancer stem cells for reducing and exploiting tumor heterogeneity

Personalized cancer medicine based on the analysis of tumors en masse is limited by tumor heterogeneity, which has become a major obstacle to effective cancer treatment. Cancer stem cells (CSC) are emerging as key drivers of inter- and intratumoral heterogeneity. CSC have unique metabolic dependencies that are required not only for specific bioenergetic/biosynthetic demands but also for sustaining their operational epigenetic traits, i.e. self-renewal, tumor-initiation, and plasticity. Given that the metabolome is the final downstream product of all the -omic layers and, therefore, most representative of the biological phenotype, we here propose that a novel approach to better understand the complexity of tumor heterogeneity is by mapping and cataloging small numbers of CSC metabolomic phenotypes. The narrower metabolomic diversity of CSC states could be employed to reduce multidimensional tumor heterogeneity into dynamic models of fewer actionable sub-phenotypes. The identification of the driver nodes that are used differentially by CSC states to metabolically regulate self-renewal and tumor initation and escape chemotherapy might open new preventive and therapeutic avenues. The mapping of CSC metabolomic states could become a pioneering strategy to reduce the dimensionality of tumor heterogeneity and improve our ability to examine changes in tumor cell populations for cancer detection, prognosis, prediction/monitoring of therapy response, and detection of therapy resistance and recurrent disease. The identification of driver metabolites and metabolic nodes accounting for a large amount of variance within the CSC metabolomic sub-phenotypes might offer new unforeseen opportunities for reducing and exploiting tumor heterogeneity via metabolic targeting of CSC.