Small-molecule agonists of mammalian Diaphanous-related (mDia) formins reveal an effective glioblastoma anti-invasion strategy.
The extensive invasive capacity of glioblastoma (GBM) makes it resistant to surgery, radiotherapy, and chemotherapy and thus makes it lethal. In vivo, GBM invasion is mediated by Rho GTPases through unidentified downstream effectors. Mammalian Diaphanous (mDia) family formins are Rho-directed effectors that regulate the F-actin cytoskeleton to support tumor cell motility. Historically, anti-invasion strategies focused upon mDia inhibition, whereas activation remained unexplored. The recent development of small molecules directly inhibiting or activating mDia-driven F-actin assembly that supports motility allows for exploration of their role in GBM. We used the formin inhibitor SMIFH2 and mDia agonists IMM-01/-02 and mDia2-DAD peptides, which disrupt autoinhibition, to examine the roles of mDia inactivation versus activation in GBM cell migration and invasion in vitro and in an ex vivo brain slice invasion model. Inhibiting mDia suppressed directional migration and spheroid invasion while preserving intrinsic random migration. mDia agonism abrogated both random intrinsic and directional migration and halted U87 spheroid invasion in ex vivo brain slices. Thus mDia agonism is a superior GBM anti-invasion strategy. We conclude that formin agonism impedes the most dangerous GBM component-tumor spread into surrounding healthy tissue. Formin activation impairs novel aspects of transformed cells and informs the development of anti-GBM invasion strategies.
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614.
Jessica D
JD
Arden
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614.
Kari I
KI
Lavik
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614.
Kaitlin A
KA
Rubinic
Department of Neurosciences, University of Toledo Health Science Campus, Toledo, OH 43614.
Nicolas
N
Chiaia
Departments of Medicine and Public Health and Homeland Security, University of Toledo Health Science Campus, Toledo, OH 43614.
Sadik A
SA
Khuder
Department of Neurosciences, University of Toledo Health Science Campus, Toledo, OH 43614.
Marthe J
MJ
Howard
Department of Surgery, University of Toledo Health Science Campus, Toledo, OH 43614.
Andrea L
AL
Nestor-Kalinoski
Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, MI 49503.
Arthur S
AS
Alberts
Department of Biochemistry and Cancer Biology, University of Toledo Health Science Campus, Toledo, OH 43614 Kathryn.eisenmann@utoledo.edu).
Kathryn M
KM
Eisenmann
D048868:Adaptor Proteins, Signal Transducing / Q000819:agonists* / Q000096:biosynthesis; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000080865:Formins; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D051381:Rats; D054852:Small Molecule Libraries / Q000494:pharmacology*; D018874:Spheroids, Cellular
D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins; D054852:Small Molecule Libraries