Cell Reports (Nov 2023)
The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable vulnerability
- Niklas Ravn-Boess,
- Nainita Roy,
- Takamitsu Hattori,
- Devin Bready,
- Hayley Donaldson,
- Christopher Lawson,
- Cathryn Lapierre,
- Aryeh Korman,
- Tori Rodrick,
- Enze Liu,
- Joshua D. Frenster,
- Gabriele Stephan,
- Jordan Wilcox,
- Alexis D. Corrado,
- Julia Cai,
- Rebecca Ronnen,
- Shuai Wang,
- Sara Haddock,
- Jonathan Sabio Ortiz,
- Orin Mishkit,
- Alireza Khodadadi-Jamayran,
- Aris Tsirigos,
- David Fenyö,
- David Zagzag,
- Julia Drube,
- Carsten Hoffmann,
- Fabiana Perna,
- Drew R. Jones,
- Richard Possemato,
- Akiko Koide,
- Shohei Koide,
- Christopher Y. Park,
- Dimitris G. Placantonakis
Affiliations
- Niklas Ravn-Boess
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Nainita Roy
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Takamitsu Hattori
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Devin Bready
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Hayley Donaldson
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Christopher Lawson
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Cathryn Lapierre
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Aryeh Korman
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
- Tori Rodrick
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
- Enze Liu
- Department of Medicine, Division of Hematology/Oncology, Indiana University, Indianapolis, IN 46202, USA
- Joshua D. Frenster
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Gabriele Stephan
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Jordan Wilcox
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Alexis D. Corrado
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Julia Cai
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Rebecca Ronnen
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Shuai Wang
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Sara Haddock
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Jonathan Sabio Ortiz
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- Orin Mishkit
- Preclinical Imaging Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
- Alireza Khodadadi-Jamayran
- Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY 10016, USA
- Aris Tsirigos
- Applied Bioinformatics Laboratories, NYU Grossman School of Medicine, New York, NY 10016, USA
- David Fenyö
- Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA; Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA
- David Zagzag
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Julia Drube
- Institute for Molecular Cell Biology, Universitätsklinikum Jena, 07745 Jena, Germany
- Carsten Hoffmann
- Institute for Molecular Cell Biology, Universitätsklinikum Jena, 07745 Jena, Germany
- Fabiana Perna
- Moffitt Cancer Center, Tampa, FL 33612, USA
- Drew R. Jones
- Metabolomics Laboratory, NYU Grossman School of Medicine, New York, NY 10016, USA
- Richard Possemato
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA
- Akiko Koide
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA
- Shohei Koide
- Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
- Christopher Y. Park
- Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA
- Dimitris G. Placantonakis
- Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU Grossman School of Medicine, New York, NY 10016, USA; Brain and Spine Tumor Center, NYU Grossman School of Medicine, New York, NY 10016, USA; Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 11
p. 113374
Abstract
Summary: Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.
