The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma.
The proliferative and invasive nature of malignant cancers drives lethality. In glioblastoma, these two processes are presumed mutually exclusive and hence termed "go or grow." We identified a molecular target that shuttles between these disparate cellular processes-the molecular motor KIF11. Inhibition of KIF11 with a highly specific small-molecule inhibitor stopped the growth of the more treatment-resistant glioblastoma tumor-initiating cells (TICs, or cancer stem cells) as well as non-TICs and impeded tumor initiation and self-renewal of the TIC population. Targeting KIF11 also hit the other arm of the "go or grow" cell fate decision by reducing glioma cell invasion. Administration of a KIF11 inhibitor to mice bearing orthotopic glioblastoma prolonged their survival. In its role as a shared molecular regulator of cell growth and motility across intratumoral heterogeneity, KIF11 is a compelling therapeutic target for glioblastoma.
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Monica
M
Venere
Department of Pathology and Laboratory, Medicine University of Kentucky College of Medicine, Lexington, KY 40506, USA.
Craig
C
Horbinski
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
James F
JF
Crish
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Xun
X
Jin
ImageIQ Inc. Cleveland, OH 44128, USA.
Amit
A
Vasanji
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Jennifer
J
Major
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Amy C
AC
Burrows
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Cathleen
C
Chang
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
John
J
Prokop
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Quilian
Q
Wu
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
Peter A
PA
Sims
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
Peter
P
Canoll
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Matthew K
MK
Summers
Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. rosenfs@ccf.org richj@ccf.org.
Steven S
SS
Rosenfeld
Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA. rosenfs@ccf.org richj@ccf.org.
Jeremy N
JN
Rich
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D002470:Cell Survival; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000473:pathology; D058105:Polymerization; D011379:Prognosis; D016019:Survival Analysis; D015854:Up-Regulation
C470243:KIF11 protein, human; D016547:Kinesins