2. Academic Validation
  3. A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

  • Cancer Cell. 2018 May 14;33(5):874-889.e7. doi: 10.1016/j.ccell.2018.03.020.
Amelie Griveau 1,  Giorgio Seano 2,  Samuel J Shelton 3,  Robert Kupp 4,  Arman Jahangiri 5,  Kirsten Obernier 3,  Shanmugarajan Krishnan 2,  Olle R Lindberg 6,  Tracy J Yuen 1,  An-Chi Tien 1,  Jennifer K Sabo 1,  Nancy Wang 2,  Ivy Chen 2,  Jonas Kloepper 2,  Louis Larrouquere 2,  Mitrajit Ghosh 2,  Itay Tirosh 7,  Emmanuelle Huillard 8,  Arturo Alvarez-Buylla 3,  Michael C Oldham 6,  Anders I Persson 9,  William A Weiss 10,  Tracy T Batchelor 11,  Anat Stemmer-Rachamimov 12,  Mario L Suvà 13,  Joanna J Phillips 14,  Manish K Aghi 5,  Shwetal Mehta 4,  Rakesh K Jain 15,  David H Rowitch 16
Affiliations

Affiliations

  • 1 Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
  • 2 Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 3 Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
  • 4 Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
  • 5 Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
  • 6 Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 8 ICM Brain and Spine Institute, 47 Boulevard de l'Hopital, 75013 Paris, France.
  • 9 Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA; Sandler Neurosciences Center, University of California San Francisco, San Francisco, CA 94143, USA.
  • 10 Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA.
  • 11 Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology and Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 12 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 13 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  • 14 Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
  • 15 Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected].
  • 16 Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of Cambridge and Wellcome Trust-MRC Stem Cell Institute, Hills Road, Cambridge CB2 0AN, UK. Electronic address: [email protected].
PMID: 29681511 DOI: 10.1016/j.ccell.2018.03.020
Abstract

Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that OLIG2+ oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, OLIG2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks OLIG2+ glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, OLIG2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular microenvironmental interactions.

Keywords

Olig2; Wnt; angiogenesis; astrocyte; blood-brain barrier; glioma; invasiveness; oligodendrocyte precursor; p53; vessel co-option.

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