Across the animal kingdom, adult tissue homeostasis is regulated by adult stem cell activity, which is commonly dysregulated in human cancers. However, identifying key regulators of stem cells in the milieu of thousands of genes dysregulated in a given cancer is challenging. Here, using a comparative genomics approach between planarian adult stem cells and patient-derived glioblastoma stem cells (GSCs), we identify and demonstrate the role of DEAD-box helicase DDX56 in regulating aspects of stemness in four stem cell systems: planarians, mouse neural stem cells, human GSCs, and a fly model of glioblastoma. In a human GSC line, DDX56 localizes to the nucleolus, and using planarians, when DDX56 is lost, stem cells dysregulate expression of ribosomal RNAs and lose nucleolar integrity prior to stem cell death. Together, a comparative genomic approach can be used to uncover conserved stemness regulators that are functional in both normal and cancer stem cells.

Many species of animals have stem cells that they maintain throughout their lives, which suggests that stem cells are an ancestral feature of all animals. From this, we take the viewpoint that cells with the biological properties of 'stemness'-self-renewal and multipotency-may share ancestral genetic circuitry. However, in practice is it very difficult to identify and compare stemness gene signatures across diverse animals and large evolutionary distances? First, it is critical to experimentally demonstrate self-renewal and potency. Second, genomic methods must be used to determine specific gene expression in stem cell types compared with non-stem cell types to determine stem cell gene enrichment. Third, gene homology must be mapped between diverse animals across large evolutionary distances. Finally, conserved genes that fulfill these criteria must be tested for role in stem cell function. It is our viewpoint that by comparing stem cell-specific gene signatures across evolution, ancestral programs of stemness can be uncovered, and ultimately, the dysregulation of stemness programs drives the state of cancer stem cells.