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
  • 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.