@article{4a847d7e753e4718ac89c058c8d71b95,
title = "GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth",
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. Li et al. show that GKAP, a scaffold protein of NMDAR, and its downstream effectors FMRP and HSF1 play important roles in the invasive growth of pancreatic tumors. In several cancer types, low NMDAR activity, based on a transcriptomic signature, associates with favorable patient prognosis.",
keywords = "FMRP, GKAP/Dlgap1, GluN2b/NR2b/Grin2b, HSF1, MK801, NMDAR, RIP1Tag2, cancer modifier, glutamate receptor, memantine, pancreatic ductal adenocarcinoma (PDAC)",
author = "Leanne Li and Qiqun Zeng and Arjun Bhutkar and Galv{\'a}n, {Jos{\'e} A.} and Eva Karamitopoulou and Daan Noordermeer and Peng, {Mei Wen} and Alessandra Piersigilli and Aurel Perren and Inti Zlobec and Hugh Robinson and Iruela-Arispe, {M. Luisa} and Douglas Hanahan",
note = "Funding Information: We thank Tyler E. Jacks (Massachusetts Institute of Technology [MIT]) for his gracious support of L.L. and A.B.; Ehud Drori for technical support; the Duboule lab (Swiss Institute for Experimental Cancer Research/{\'E}cole Polytechnique F{\'e}d{\'e}rale de Lausanne [EPFL]) for assistance with ChIP experiments; A. Necsulea (EPFL and Universit{\'e} de Lyon) for bioinformatics analysis; J. Delafontaine and J. Rougement (EPFL) for transcription factor analysis; the De Palma lab (EPFL) for help with lentiviral infection; M.G.H. Chun (University of California, San Francisco [UCSF] and Salk Institute), P. Olson (UCSF), and K. Shchors (EPFL) for cell line and reagents; S. Saqafi (EPFL) for bioinformatic advice; A. Jaegger (MIT), A. Balmain (UCSF), G. Ciriello (University of Lausanne [UNIL]), and I. Michael (EPFL) for constructive comments on the manuscript; and the Genome Core at UNIL and the Histology and Animal Care Facilities at EPFL for technical services. The PDAC TMA was made available through Tissue Biobank Bern (TBB, University of Bern). This research was supported by an Advanced Grant from the European Research Council (grant numbers: 587516/322491 ). ",
year = "2018",
month = apr,
day = "9",
doi = "10.1016/j.ccell.2018.02.011",
language = "English (US)",
volume = "33",
pages = "736--751.e5",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}