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

被引：60

作者：

Li, Leanne ^{[1
,2
]}

Zeng, Qiqun ^{[1
]}

Bhutkar, Arjun ^{[2
]}

Galvan, Jose A. ^{[3
]}

Karamitopoulou, Eva ^{[3
]}

Noordermeer, Daan ^{[1
,8
]}

Peng, Mei-Wen ^{[1
]}

Piersigilli, Alessandra ^{[3
,4
,9
]}

Perren, Aurel ^{[3
]}

Zlobec, Inti ^{[3
]}

Robinson, Hugh ^{[5
]}

Iruela-Arispe, M. Luisa ^{[6
,7
]}

Hanahan, Douglas ^{[1
]}

机构：

[1] Swiss Fed Inst Technol Lausanne EPFL, Sch Life Sci, Swiss Inst Canc Res, CH-1015 Lausanne, Switzerland

[2] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[3] Univ Bern, Inst Pathol, Murtenstr 31, CH-3008 Bern, Switzerland

[4] Swiss Fed Inst Technol Lausanne EPFL, Sch Life Sci, CH-1015 Lausanne, Switzerland

[5] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England

[6] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA

[7] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[8] Univ Paris Sud, Inst Integrat Biol Cell I2BC, CNRS, CEA, F-91198 Gif Sur Yvette, France

[9] Weill Cornell Med Coll, New York, NY 10065 USA

来源：

CANCER CELL | 2018年 / 33卷 / 04期

基金：

欧洲研究理事会;

关键词：

PANCREATIC NEUROENDOCRINE; FRAGILE-X; SYNAPTIC PLASTICITY; CANCER; PROTEIN; METASTASIS; EXPRESSION; REVEALS; MODELS; ADENOCARCINOMA;

D O I：

10.1016/j.ccell.2018.02.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：736 / +

页数：21

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