Critical Role for GAB2 in Neuroblastoma Pathogenesis through the Promotion of SHP2/MYCN Cooperation.
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.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.
Xiaoling
X
Zhang
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.
Zhiwei
Z
Dong
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Cheng
C
Zhang
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Choong Yong
CY
Ung
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Shuning
S
He
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Ting
T
Tao
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Andre M
AM
Oliveira
Department of Dermatology, Mayo Clinic, Rochester, MN 55902, USA.
Alexander
A
Meves
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.
Baoan
B
Ji
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
A Thomas
AT
Look
Department of Molecular Pharmacology and Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Hu
H
Li
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: benjamin.neel@nyumc.org.
Benjamin G
BG
Neel
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.
Shizhen
S
Zhu
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D005784:Gene Amplification / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D000071447:N-Myc Proto-Oncogene Protein / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D012307:Risk Factors; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
C000600493:CBLC137; D002227:Carbazoles; D002352:Carrier Proteins; C000624908:Gab2 protein, zebrafish; D000071447:N-Myc Proto-Oncogene Protein; D029961:Zebrafish Proteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C000588865:protein tyrosine phosphatase, non-receptor type 11, a, zebrafish
Gab2; MYCN; RAS-ERK pathway; Shp2; neuroblastoma; ptpn11; zebrafish