TMIC-43. HEDGEHOG LIGANDS FROM GLIOBLASTOMA CELLS INDUCE ASTROCYTES INHIBITION OF CANCER STEM CELLS

Abstract BACKGROUND The Hedgehog pathway directs gene expression programs that are essential for glioblastoma stem cells in vitro, but a clinical trial suggested inhibition does not improve outcomes (ABTC-0904). In pancreatic and bladder cancer, signaling through the tumor microenvironment induces stromal morphogens to inhibit cancer cell proliferation. Thus, we hypothesized may proliferation vivo. METHODS was studied using patient-derived, fluorescently-labeled IDH wild-type (GBM6, SF11956, SF11907, GPMP004, GPMP005) vivo after intracranial implantation mice, or 3D co-culture with iPSC-derived organoids comprised of human astrocytes neurons. Genetic loss-of-function experiments were performed CRISPR interference. Cell proliferation, marker expression, Sonic (SHH) primary cilia architecture assessed immunofluorescence, confocal microscopy, live-cell imaging. morphogen QPCR single-cell RNA sequencing. Pharmacologic vismodegib pathway, FK506 induce expression. RESULTS Vismodegib increased astrocyte organoids. Single-cell sequencing demonstrated induced target genes markers cells, astrocytes, which also expressed cilia. CRISPRi suppression SHH Neither nor vitro neuron inhibiting effects CONCLUSIONS from signals