GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth.
Galván, José A
Iruela-Arispe, M Luisa
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Li, L., Zeng, Q., Bhutkar, A., Galván, J. A., Karamitopoulou, E., Noordermeer, D., Peng, M., et al. (2018). GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth.. Cancer Cell, 33 (4), 736-751.e5. https://doi.org/10.1016/j.ccell.2018.02.011
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.
Cell Line, Tumor, Animals, Humans, Mice, Carcinoma, Neuroendocrine, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Neoplasm Invasiveness, Receptors, N-Methyl-D-Aspartate, Antineoplastic Agents, Prognosis, Survival Analysis, Gene Expression Profiling, Sequence Analysis, RNA, Neoplasm Transplantation, Signal Transduction, Gene Expression Regulation, Neoplastic, Fragile X Mental Retardation Protein, SAP90-PSD95 Associated Proteins, Heat Shock Transcription Factors
External DOI: https://doi.org/10.1016/j.ccell.2018.02.011
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277627
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: http://creativecommons.org/licenses/by-nc-nd/4.0/
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