TGF-β Determines the Pro-migratory Potential of bFGF Signaling in Medulloblastoma
Karthiga Santhana Kumar,
Anuja Neve,
Ana S. Guerreiro Stucklin,
Claudia M. Kuzan-Fischer,
Elisabeth J. Rushing,
Michael D. Taylor,
Dimitra Tripolitsioti,
Lena Behrmann,
Daniel Kirschenbaum,
Michael A. Grotzer,
Martin Baumgartner
Affiliations
Karthiga Santhana Kumar
Paediatric Neuro-Oncology Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland
Anuja Neve
Paediatric Neuro-Oncology Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland
Ana S. Guerreiro Stucklin
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada
Claudia M. Kuzan-Fischer
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Department of Surgery, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Elisabeth J. Rushing
Institute of Neuropathology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
Michael D. Taylor
The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; Department of Surgery, Department of Laboratory Medicine and Pathobiology, and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Dimitra Tripolitsioti
Paediatric Neuro-Oncology Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland
Lena Behrmann
Paediatric Leukaemia Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland
Daniel Kirschenbaum
Institute of Neuropathology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
Michael A. Grotzer
Paediatric Neuro-Oncology Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland; Department of Oncology, University Children’s Hospital Zürich, Steinwiesstrasse 75, CH-8032 Zürich, Switzerland
Martin Baumgartner
Paediatric Neuro-Oncology Research Group, Department of Oncology, Children’s Research Center, University Children’s Hospital Zürich, August-Forel Strasse 1, CH-8008 Zürich, Switzerland; Corresponding author
Summary: The microenvironment shapes cell behavior and determines metastatic outcomes of tumors. We addressed how microenvironmental cues control tumor cell invasion in pediatric medulloblastoma (MB). We show that bFGF promotes MB tumor cell invasion through FGF receptor (FGFR) in vitro and that blockade of FGFR represses brain tissue infiltration in vivo. TGF-β regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-β pathway causes ROCK activation and cortical translocation of ERK1/2, which antagonizes FGFR signaling by inactivating FGFR substrate 2 (FRS2), and promotes a contractile, non-motile phenotype. Under high bFGF, negative-feedback regulation of FRS2 by bFGF-induced ERK1/2 causes repression of the FGFR pathway. Under these conditions, TGF-β counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-β signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling. : Santhana Kumar et al. describe how growth factors in the microenvironment of medulloblastoma, the most common malignant brain tumor in children, are sensed by the tumor cells and how they respond to these factors. They identify the adaptor protein FRS2 as a key molecule controlling growth factor-induced tissue infiltration. Keywords: medulloblastoma, migration, invasion, FGFR1 signaling, FRS2, bFGF, TGF-β signaling, tumor microenvironment, organotypic cerebellum slice culture
