@article{fe3fb46bee9a4e83ae74f07db9933f58,
title = "Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation",
abstract = "Growing evidence suggests a major role for Src-homology-2-domain-containing phosphatase 2 (SHP2/PTPN11) in MYCN-driven high-risk neuroblastoma, although biologic confirmation and a plausible mechanism for this contribution are lacking. Using a zebrafish model of MYCN-overexpressing neuroblastoma, we demonstrate that mutant ptpn11 expression in the adrenal gland analog of MYCN transgenic fish promotes the proliferation of hyperplastic neuroblasts, accelerates neuroblastomagenesis, and increases tumor penetrance. We identify a similar mechanism in tumors with wild-type ptpn11 and dysregulated Gab2, which encodes a Shp2 activator that is overexpressed in human neuroblastomas. In MYCN transgenic fish, Gab2 overexpression activated the Shp2-Ras-Erk pathway, enhanced neuroblastoma induction, and increased tumor penetrance. We conclude that MYCN cooperates with either GAB2-activated or mutant SHP2 in human neuroblastomagenesis. Our findings further suggest that combined inhibition of MYCN and the SHP2-RAS-ERK pathway could provide effective targeted therapy for high-risk neuroblastoma patients with MYCN amplification and aberrant SHP2 activation.",
keywords = "Gab2, MYCN, RAS-ERK pathway, Shp2, neuroblastoma, ptpn11, zebrafish",
author = "Xiaoling Zhang and Zhiwei Dong and Cheng Zhang and Ung, {Choong Yong} and Shuning He and Ting Tao and Oliveira, {Andre M.} and Alexander Meves and Baoan Ji and Look, {A. Thomas} and Hu Li and Neel, {Benjamin G.} and Shizhen Zhu",
note = "Funding Information: We thank J.R. Gilbert for editorial review of the manuscript and critical comments. This work was supported by grant K99/R00CA178189 (S.Z.) from the National Cancer Institute; young investigator awards from Alex's Lemonade Stand Foundation (S.Z.) and the CureSearch for Children's Cancer Foundation (S.Z.); a V Scholar award from the V Foundation for Cancer Research (S.Z.) and pilot project awards from the Fraternal Order of Eagles (S.Z.) and the Mayo Center for Biomedical Discovery (S.Z.); support from the Mayo Clinic Cancer Center, Center for Biomedical Discovery, and Center for Individualized Medicine (S.Z.); grant R01 CA180692 (A.T.L.) from the National Cancer Institute; an Alex's Lemonade Stand Foundation Innovation Award (A.T.L.); a fellowship from the Friends for Life and the Friends of DFCI (T.T.); a grant from the Children's Neuroblastoma Cancer Foundation (T.T.); grant CA196631-01A1 (H.L.) from the NIH; and grant R37 CA49152 (B.G.N.) from the NIH. During part of this work, B.G.N. was a Canada Research Chair, Tier 1, and was partially supported by the Princess Margaret Cancer Foundation. We also thank Incuron for providing the CBL0137 compound for our study. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = mar,
day = "21",
doi = "10.1016/j.celrep.2017.02.065",
language = "English (US)",
volume = "18",
pages = "2932--2942",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}