GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

Leanne Li; Qiqun Zeng; Arjun Bhutkar; José A Galván; Eva Karamitopoulou; Daan Noordermeer; Mei-Wen Peng; Alessandra Piersigilli; Aurel Perren; Inti Zlobec; Hugh Robinson; M Luisa Iruela-Arispe; Douglas Hanahan

doi:10.1016/j.ccell.2018.02.011

GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth

Cancer Cell. 2018 Apr 9;33(4):736-751.e5. doi: 10.1016/j.ccell.2018.02.011. Epub 2018 Mar 29.

Authors

Affiliations

¹ Swiss Institute of Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland.
⁴ Institute of Pathology, University of Bern, Murtenstrasse 31, 3008 Bern, Switzerland; School of Life Science, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland.
⁵ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
⁶ Department of Molecular, Cell and Developmental Biology, Jonsson Comprehensive Cancer Center and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
⁷ Swiss Institute of Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne, Switzerland. Electronic address: [email protected].

Abstract

Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types.

Keywords: FMRP; GKAP/Dlgap1; GluN2b/NR2b/Grin2b; HSF1; MK801; NMDAR; RIP1Tag2; cancer modifier; glutamate receptor; memantine; pancreatic ductal adenocarcinoma (PDAC).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Carcinoma, Neuroendocrine / drug therapy
Carcinoma, Neuroendocrine / genetics*
Carcinoma, Neuroendocrine / metabolism
Carcinoma, Pancreatic Ductal / drug therapy
Carcinoma, Pancreatic Ductal / genetics*
Carcinoma, Pancreatic Ductal / metabolism
Cell Line, Tumor
Fragile X Mental Retardation Protein / genetics*
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic / drug effects
Heat Shock Transcription Factors / genetics*
Humans
Mice
Neoplasm Invasiveness
Neoplasm Transplantation
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / genetics*
Pancreatic Neoplasms / metabolism
Prognosis
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism
SAP90-PSD95 Associated Proteins / genetics*
Sequence Analysis, RNA / methods
Signal Transduction* / drug effects
Survival Analysis

Substances

Antineoplastic Agents
DLGAP1 protein, human
FMR1 protein, human
HSF1 protein, human
Heat Shock Transcription Factors
Receptors, N-Methyl-D-Aspartate
SAP90-PSD95 Associated Proteins
Fragile X Mental Retardation Protein

Grants and funding

P30 CA016042/CA/NCI NIH HHS/United States