CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells
Elinn Johansson,
Elisa S. Grassi,
Vasiliki Pantazopoulou,
Bei Tong,
David Lindgren,
Tracy J. Berg,
Elin J. Pietras,
Håkan Axelson,
Alexander Pietras
Affiliations
Elinn Johansson
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Elisa S. Grassi
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Vasiliki Pantazopoulou
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Bei Tong
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
David Lindgren
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Tracy J. Berg
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Elin J. Pietras
Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen 2200, Denmark
Håkan Axelson
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Alexander Pietras
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Scheelevägen 2, Medicon Village 404:C3, 223 63 Lund, Sweden
Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen.
