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Cell Rep. 2017 Mar 21;18(12):2932-2942. doi: 10.1016/j.celrep.2017.02.065.

Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.
2
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
5
Department of Dermatology, Mayo Clinic, Rochester, MN 55902, USA.
6
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: benjamin.neel@nyumc.org.
7
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA. Electronic address: zhu.shizhen@mayo.edu.

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

PMID:
28329685
PMCID:
PMC5393048
DOI:
10.1016/j.celrep.2017.02.065
[Indexed for MEDLINE]
Free PMC Article

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