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

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

Author information

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: douglas.hanahan@epfl.ch.

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)

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