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

摘要

class="head no_bottom_margin" id="sec1title">Significance>Genetic linkage analyses have associated multiple cancer modifier loci with disease susceptibility, malignant phenotypes, and responses to treatment. However, functional validation of cancer modifier genes has been challenging and insights into underlying mechanistic basis limited. In this proof-of-concept study, we used genetically engineered mouse models derived from distinct strain backgrounds to explore the validation process: we began with a candidate invasion modifier gene, Dlgap1 (which encodes GKAP protein), suggested by genetic linkage analysis, and went on to establish its role as a modifier of invasive growth orchestrated by NMDAR signaling. Using refined bioinformatics algorithms, we identified a signature for tumors lacking NMDAR-GKAP pathway activity that predicts better prognosis in various cancer types, suggestive of broader involvement of this pathway in malignancy.