摘要:
Adult stem cells (ASCs) that self renew indefinitely and generate differentiated cell types are present in species of every phylum identified and, thus, likely share a common evolutionary origin. Cancer stem cells (CSCs), a cell type known to drive tumourigenesis and recurrence, also share these functional properties with ASCs, as well as molecular characteristics, albeit in a dysregulated manner. It is plausible that normal ASCs and CSCs utilize a common genetic circuitry to mediate their shared functional properties, and a comparative genomics strategy may uncover conserved stemness factors required for regulating stemness in normal and cancer stem cells across evolution. Here, I identified transcripts that have enriched expression and a human ortholog in planarian ASCs and cross-referenced this list to genes that are upregulated in glioblastoma stem cells (GSCs) compared to their normal stem cell counterparts. In total, I identified 76 putative stemness regulators common in both systems and I systematically knocked down expression of candidate genes in planarians by RNAi. I found 29/76 resulted in stem cell dysfunction leading to planarian death. DDX56 encodes a DEAD-box RNA helicase, and high DDX56 expression is correlated with worse clinical outcome in GBM patients. I demonstrated planarian ddx56 is required for ASC function, and ddx56(RNAi) caused impaired differentiation, reduced proliferation and ASC loss, as well as disrupted nucleolar integrity and dysregulation of ribosomal components. In patient-derived GSCs, DDX56 localized to the nucleolus, and knockout suppressed CSC growth and self-renewal in vitro. Together, I suggest a role for DDX56 in ribosomal biogenesis, where upregulation of DDX56 in a cancer context reduces nucleolar stress. Another candidate, smarcc2, encodes a core component of the BAF chromatin remodeling complex. In planarian ASCs, I determined the BAF complex regulates chromatin accessibility and therefore expression of key target genes