Niche-derived soluble DLK1 promotes glioma stemness and growth

Tumor cell behaviors associated with aggressive tumor growth such as proliferation, therapeutic resistance, and stemness are regulated in part by soluble factors derived from the tumor microenvironment. Tumor-associated astrocytes represent a major component of the glioma tumor microenvironment, and astrocytes have an active role in maintenance of normal neural stem cells in the stem cell niche, in part via secretion of soluble Delta-like Non-Canonical Notch Ligand 1 (DLK1). We found that astrocytes, when exposed to stresses of the tumor microenvironment such as hypoxia or ionizing radiation (IR), increased secretion of soluble DLK1. Tumor-associated astrocytes in a glioma mouse model expressed DLK1 in perinecrotic (hypoxic) and perivascular tumor areas. Glioma cells exposed to recombinant DLK1 displayed increased proliferation, enhanced sphere and colony formation abilities, and increased levels of stem cell marker genes. Mechanistically, DLK1-mediated effects on glioma cells involved increased and prolonged stabilization of Hypoxia-Inducible Factor 2alpha (HIF-2alpha), and inhibition of HIF-2alpha activity abolished effects of DLK1 in hypoxia. Forced expression of soluble DLK1 resulted in more aggressive tumor growth and shortened survival in a genetically engineered mouse model of glioma. Together, our data support DLK1 as a soluble mediator of glioma aggressiveness derived from the tumor microenvironment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/258608v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@18902b8org.highwire.dtl.DTLVardef@11b21corg.highwire.dtl.DTLVardef@1c44f60org.highwire.dtl.DTLVardef@1376300_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAstrocytes secrete DLK1 after exposure to hypoxia or irradiation C_LIO_LISoluble DLK1 promotes stemness in glioma, in part by increasing HIF-2alpha stabilization. C_LIO_LIHigh levels of soluble DLK1 are associated with tumor aggressiveness and lethality. C_LI