Journal Article

EXTH-31. TARGETING THE FORMIN-DIRECTED CYTOSKELETON WITH SMALL MOLECULE AGONISTS BLOCKS GLIOBLASTOMA PATIENT-DERIVED NEUROSPHERE INVASION

Kathryn Eisenmann, Jason Schroeder, Krista Pettee, Kathryn Becker and Christine Sattler

in Neuro-Oncology

Volume 20, issue suppl_6 Published in print November 2018 | ISSN: 1522-8517
Published online November 2018 | e-ISSN: 1523-5866 | DOI: https://dx.doi.org/10.1093/neuonc/noy148.380
EXTH-31. TARGETING THE FORMIN-DIRECTED CYTOSKELETON WITH SMALL MOLECULE AGONISTS BLOCKS GLIOBLASTOMA PATIENT-DERIVED NEUROSPHERE INVASION

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Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and aggressive treatment only extends survival by months. While metastasis outside the CNS is rare, GBM is highly invasive. Failure of current GBM therapies to target invasive cells partly explains why these treatments confer only minimal survival advantages: invasive tumors lack easily-defined margins, making complete surgical resection impossible, and invasive GBM cells are inherently more chemo- and radioresistant. Therefore, anti-invasive therapies may effectively sensitize GBM cells to conventional therapies and improve survival. Anti-invasive treatments are thus greatly needed, and cellular mechanisms governing GBM invasion represent understudied therapeutic targets. Much work has centered upon how Rho GTPases mediate GBM invasion, yet the roles of downstream Rho effector proteins are poorly understood and represent potential novel therapeutic targets. A role for the mammalian Diaphanous (mDia)-related formin family of Rho GTPase effector proteins has emerged in metastatic disease. mDias are nanomachines generating linear actin filaments to drive protrusive cytoskeletal structures underlying tumor cell invasion. Using novel small molecule mDia agonists (IMMs, orn intramimics) that induce endogenous mDia functional activities, including F-actin polymerization, we demonstrated roles for mDia in driving polarized GBM cell migration. mDia agonism halted GBM spheroid invasion in three-dimensional (3D) in vitro and ex vivo rat brain slice models. Here, we evaluate if GBM patient cell lines are sensitive to formin agonism to halt invasion. Four patient-derived GBM cell lines were isolated as single cell suspensions, and spontaneously formed non-adherent neurospheres. Neurospheres were embedded in 3D-matrices and allowed to invade +/- IMMs. IMMs dramatically inhibited GBM patient neurosphere invasion, significantly impacting both distance single cells migrated from neurosphere edges and lengths of actin-enriched cellular extensions into matrices. Thus, mDia agonism effectively disrupted multiple aspects of patient-derived GBM neurosphere invasion in vitro, warranting further investigation in patient-derived xenografts.

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Subjects: Medical Oncology ; Neurology

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