期刊
CELL REPORTS
卷 23, 期 13, 页码 3798-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.05.083
关键词
-
类别
资金
- Garron Family Cancer Research Center at the Hospital for Sick Children
- Worldwide Cancer Research
- NIH [R01CA148699, R01CA159859]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- b.r.a.i.n.child
- Meagan's Walk
- Genome Canada
- Genome BC
- V-Foundation for Cancer Research [T2017-020]
- Government of Ontario
- Canadian Cancer Society Research Institute Impact grant
- Government of Canada through Genome Canada [SU2C-AACR-DT1113, SU2C-AACR-DT-19-15]
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
- Swiss National Science Foundation [SNF_31004A-144090/1, 165860/1]
- Werner Foundation
- Hedy Berger-Janser Foundation
- Sassella Foundation
- Swiss Cancer League [CHKL-2834-02-2016]
- Childhood Cancer Switzerland
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-beta regulates pro-migratory bFGF function in a context-dependent manner. Under low bFGF, the non-canonical TGF-beta 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-beta counters inactivation of FRS2 and restores pro-migratory signaling. These findings pinpoint coincidence detection of bFGF and TGF-beta signaling by FRS2 as a mechanism that controls tumor cell invasion. Thus, targeting FRS2 represents an emerging strategy to abrogate aberrant FGFR signaling.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据