Myosin 10 Regulates Invasion, Mitosis, and Metabolic Signaling in Glioblastoma
Rajappa S. Kenchappa,
Panagiotis Mistriotis,
Emily Wisniewski,
Santanu Bhattacharya,
Tanmay Kulkarni,
Rita West,
Amanda Luu,
Meghan Conlon,
Ernest Heimsath,
James F. Crish,
Hannah S. Picariello,
Athanassios Dovas,
Natanael Zarco,
Montserrat Lara-Velazquez,
Alfredo Quiñones-Hinojosa,
John A. Hammer,
Debrabrata Mukhopadhyay,
Richard E. Cheney,
Konstantinos Konstantopoulos,
Peter Canoll,
Steven S. Rosenfeld
Affiliations
Rajappa S. Kenchappa
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Panagiotis Mistriotis
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Emily Wisniewski
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Santanu Bhattacharya
Departments of Biochemistry and Molecular Biology and Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL 32224, USA
Tanmay Kulkarni
Departments of Biochemistry and Molecular Biology and Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL 32224, USA
Rita West
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Amanda Luu
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Meghan Conlon
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Ernest Heimsath
Department of Cell Biology and Physiology, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
James F. Crish
Department of Cancer Biology, Lerner Research Institute, Cleveland, OH 44106, USA
Hannah S. Picariello
Department of Cancer Biology, Lerner Research Institute, Cleveland, OH 44106, USA
Athanassios Dovas
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Natanael Zarco
Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
Montserrat Lara-Velazquez
Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
Alfredo Quiñones-Hinojosa
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA
John A. Hammer
Cell and Developmental Biology Center, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
Debrabrata Mukhopadhyay
Departments of Biochemistry and Molecular Biology and Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL 32224, USA
Richard E. Cheney
Department of Cell Biology and Physiology, and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA
Konstantinos Konstantopoulos
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
Peter Canoll
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Steven S. Rosenfeld
Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA; Department of Neurosurgery, Mayo Clinic, Jacksonville, FL 32224, USA; Corresponding author
Summary: Invasion and proliferation are defining phenotypes of cancer, and in glioblastoma blocking one stimulates the other, implying that effective therapy must inhibit both, ideally through a single target that is also dispensable for normal tissue function. The molecular motor myosin 10 meets these criteria. Myosin 10 knockout mice can survive to adulthood, implying that normal cells can compensate for its loss; its deletion impairs invasion, slows proliferation, and prolongs survival in murine models of glioblastoma. Myosin 10 deletion also enhances tumor dependency on the DNA damage and the metabolic stress responses and induces synthetic lethality when combined with inhibitors of these processes. Our results thus demonstrate that targeting myosin 10 is active against glioblastoma by itself, synergizes with other clinically available therapeutics, may have acceptable side effects in normal tissues, and has potential as a heretofore unexplored therapeutic approach for this disease.
