GSE120647
Glioblastoma multiforme cancer stem cells from different patients exhibit consistent gene expression changes following Hes3 RNA interference
Cancer cells are plastic, switching between signaling pathways to regulate growth under different conditions. In the tumor microenvironment this likely helps them evade therapies that target specific pathways. We must identify all possible signaling states and utilize them in drug screening programs to. One such state is characterized by expression of the transcription factor Hes3 and sensitivity to Hes3 knockdown and can be modeled in vitro by the use of defined culture conditions. Here we modeled this state in vitro, characterized it, and used it to identify drugs that target it. We cultured three primary human brain cancer cell lines, each from a different patient, under three different culture conditions (low, medium, and high Hes3 expression) and characterized gene regulation (RNA sequencing) and mechanical phenotype (real-time deformability assay). We also assessed gene expression regulation following Hes3 knockdown in conditions that maintain high Hes3 expression. We then employed a commonly used human brain tumor cell line to screen 1,600 FDA-approved compounds that specifically target the Hes3-high state in two different culture conditions (high and low Hes3). Cells from multiple patients behave similarly when placed under distinct culture conditions, in the assays described. We identified 37 FDA-approved compounds that specifically kill cancer cells in conditions characterized by high but not those characterized by low Hes3 expression. Our work reveals novel, potentially core signaling states in cancer, a strategy to identify treatments against them, and a set of putative drugs for potential repurposing. Overall design: RNA-seq data from quadruplicate samples of different human glioblastoma multiforme primary cancer stem cell lines grown in defined culture conditions and treated with either Hes3 or scrambled control siRNA.