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

Authors

• Amelie Griveau, 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.
• Giorgio Seano, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Samuel J. Shelton, 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.
• Robert Kupp, Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.Follow
• Arman Jahangiri, Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
• Kirsten Obernier, 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.
• Shanmugarajan Krishnan, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Olle R. Lindberg, 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.
• Tracy J. Yuen, 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.
• An-Chi Tien, 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.
• Jennifer K. Sabo, 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.
• Nancy Wang, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Ivy Chen, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Jonas Kloepper, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Louis Larrouquere, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Mitrajit Ghosh, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Itay Tirosh, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
• Emmanuelle Huillard, ICM Brain and Spine Institute, 47 Boulevard de l'Hopital, 75013 Paris, France.
• Arturo Alvarez-Buylla, 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.
• Michael C. Oldham, 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.
• Anders I. Persson, 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.
• William A. Weiss, 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.
• Tracy T. Batchelor, 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.
• Anat Stemmer-Rachamimov, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
• Mario L. Suvà, 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.
• Joanna J. Phillips, 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.
• Manish K. Aghi, Department of Neurological Surgery and Brain Tumor Research Center, University of California San Francisco, San Francisco, CA 94143, USA.
• Shwetal Mehta, Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
• Rakesh K. Jain, Edwin L. Steele Laboratories of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Electronic address: jain@steele.mgh.harvard.edu.
• David H. Rowitch, 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: dhr25@medschl.cam.ac.uk.

Document Type

Article

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

Medical Subject Headings

Animals; Bevacizumab (pharmacology); Blood-Brain Barrier (metabolism); Brain Neoplasms (blood supply, drug therapy, metabolism); Cell Line, Tumor; Gene Expression Regulation, Neoplastic (drug effects); Glioma (blood supply, drug therapy, metabolism); Humans; Mice; Neoplasm Transplantation; Oligodendrocyte Transcription Factor 2 (genetics, metabolism); Oligodendroglia (microbiology); Temozolomide (pharmacology); Tumor Cells, Cultured; Tumor Microenvironment; Wnt Proteins (genetics, metabolism); Wnt Signaling Pathway (drug effects)

Publication Date

5-14-2018

Publication Title

Cancer cell

E-ISSN

1878-3686

Volume

33

Issue

5

First Page

874

Last Page

889.e7

PubMed ID

29681511

Digital Object Identifier (DOI)

10.1016/j.ccell.2018.03.020

Recommended Citation

Griveau, Amelie; Seano, Giorgio; Shelton, Samuel J.; Kupp, Robert; Jahangiri, Arman; Obernier, Kirsten; Krishnan, Shanmugarajan; Lindberg, Olle R.; Yuen, Tracy J.; Tien, An-Chi; Sabo, Jennifer K.; Wang, Nancy; Chen, Ivy; Kloepper, Jonas; Larrouquere, Louis; Ghosh, Mitrajit; Tirosh, Itay; Huillard, Emmanuelle; Alvarez-Buylla, Arturo; Oldham, Michael C.; Persson, Anders I.; Weiss, William A.; Batchelor, Tracy T.; Stemmer-Rachamimov, Anat; Suvà, Mario L.; Phillips, Joanna J.; Aghi, Manish K.; Mehta, Shwetal; Jain, Rakesh K.; and Rowitch, David H., "A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment" (2018). Translational Neuroscience. 1577.
https://scholar.barrowneuro.org/neurobiology/1577