title: The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma.
abstract: Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Karthiga
authors.initials: K
authors.lastname: Santhana Kumar
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Tripolitsioti
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.|Current address: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Grählert
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Katja B
authors.initials: KB
authors.lastname: Egli
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fiaschetti
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grotzer
authors.affiliation: Department of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland.|University Children's Hospital Zürich, Department of Oncology, Children's Research Center, Neuro-Oncology group, August-Forel Strasse 1, CH-8008 Zürich, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Baumgartner
keywords: Actin dynamics; Cancer cell dissemination; Cell motility; MAP4K4; Medulloblastoma; c-Met