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

Summary

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.

Graphical Abstract

Highlights

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  GKAP governs invasive growth of pancreatic cancers via NMDAR signaling

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  HSF1 and FMRP are downstream effectors of the NMDAR-GKAP axis

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  A multigene signature of low/inhibited NMDAR-GKAP pathway activity is reported

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  A low-NMDAR-GKAP signature predicts better survival for various human cancers

Abstract

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.