GKAP acts as a genetic modulator of NMDAR signaling to govern tumor invasiveness

Genetic linkage analysis suggested that GKAP, a scaffold protein of the NMDA receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine cancer (PanNET). Here we establish that GKAP governs invasive growth and treatment response of PanNET via its pivotal role in regulating the NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we distilled gene expression signatures orchestrated by the NMDAR-GKAP axis, in addition to identifying two downstream effectors FMRP and HSF-1. Additionally, GKAP, FMRP, and HSF1 are functionally implicated in invasiveness of pancreatic ductal adenocarcinoma. Finally, gene expression signatures in tumors with low NMDAR activity are significantly associated with favorable patient prognosis in several cancer types. mPanNET tumors from different strain backgrounds: C57Bl/6 (B6) and C3HeB/Fe (C3H). Within B6 tumors, either treated with a potent NMDAR antagonist MK801 or untreated/saline-treated controls.

遗传连锁分析显示，N-甲基-D-天冬氨酸受体（NMDAR）的支架蛋白GKAP，在胰腺神经内分泌癌（PanNET）小鼠模型中是肿瘤侵袭的潜在调控因子。本研究证实，GKAP通过调控NMDAR通路活性的关键作用，调控胰腺神经内分泌癌的侵袭性生长与治疗响应。本研究结合GKAP基因敲低与NMDAR药物抑制实验，凝练出由NMDAR-GKAP轴调控的基因表达特征，同时鉴定出两个下游效应蛋白FMRP（Fragile X Mental Retardation Protein）与HSF-1（Heat Shock Factor 1）。此外，GKAP、FMRP与HSF1在胰腺导管腺癌的侵袭性进程中发挥功能性作用。最后，在多种癌症类型中，NMDAR活性较低的肿瘤的基因表达特征与患者良好预后显著相关。本研究使用的mPanNET肿瘤源自两种不同遗传背景的小鼠品系：C57Bl/6（B6）与C3HeB/Fe（C3H），其中B6组肿瘤分别接受强效NMDAR拮抗剂MK801处理，或不予处理/以生理盐水处理作为对照。