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

Amelie Griveau; Giorgio Seano; Samuel J Shelton; Robert Kupp; Arman Jahangiri; Kirsten Obernier; Shanmugarajan Krishnan; Olle R Lindberg; Tracy J Yuen; An-Chi Tien; Jennifer K Sabo; Nancy Wang; Ivy Chen; Jonas Kloepper; Louis Larrouquere; Mitrajit Ghosh; Itay Tirosh; Emmanuelle Huillard; Arturo Alvarez-Buylla; Michael C Oldham; Anders I Persson; William A Weiss; Tracy T Batchelor; Anat Stemmer-Rachamimov; Mario L Suvà; Joanna J Phillips; Manish K Aghi; Shwetal Mehta; Rakesh K Jain; David H Rowitch

doi:10.1016/j.ccell.2018.03.020

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. Epub 2018 Apr 19.

Authors

Amelie Griveau¹, Giorgio Seano², Samuel J Shelton³, Robert Kupp⁴, Arman Jahangiri⁵, Kirsten Obernier³, Shanmugarajan Krishnan², Olle R Lindberg⁶, Tracy J Yuen¹, An-Chi Tien¹, Jennifer K Sabo¹, Nancy Wang², Ivy Chen², Jonas Kloepper², Louis Larrouquere², Mitrajit Ghosh², Itay Tirosh⁷, Emmanuelle Huillard⁸, Arturo Alvarez-Buylla³, Michael C Oldham⁶, Anders I Persson⁹, William A Weiss¹⁰, Tracy T Batchelor¹¹, Anat Stemmer-Rachamimov¹², Mario L Suvà¹³, Joanna J Phillips¹⁴, Manish K Aghi⁵, Shwetal Mehta⁴, Rakesh K Jain¹⁵, David H Rowitch¹⁶

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: jain@steele.mgh.harvard.edu.
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: dhr25@medschl.cam.ac.uk.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

OLIG2 protein, human
Oligodendrocyte Transcription Factor 2
WNT7A protein, human
WNT7B protein, human
Wnt Proteins
Bevacizumab
Temozolomide

Abstract

Publication types

MeSH terms

Substances

Grants and funding