Activation of the glutamate receptor NMDAR promotes cancer cell proliferation and invasion.
Major finding: Activation of the glutamate receptor NMDAR promotes cancer cell proliferation and invasion.
Mechanism: Interstitial flow induces autocrine glutamate secretion and NMDAR signaling via MAPK and CAMK.
Impact: Inhibition of NMDAR signaling at the invasive tumor periphery shows antitumor activity in mice.
Secretion of glutamate by cancer cells promotes tumor growth and invasion via activation of its G-protein-coupled and ionotropic receptors. N-methyl-D-aspartate receptor (NMDAR) is a glutamate receptor that regulates neuronal function and plasticity and is expressed in various cancers, but the role of glutamate-driven NMDAR signaling in tumorigenesis is unknown. Li and Hanahan found that elevated expression of NMDAR, in particular the NR2b subunit, localized to the invasive tumor periphery in a genetically engineered mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in several types of human cancers and was correlated with decreased patient survival. Inhibition of NMDAR with a selective antagonist diminished the proliferation and invasion of murine PNET cells and a subset of human cancer cell lines in vitro. NMDAR-dependent regulation of invasion was mediated by increased expression of vesicular glutamate transporters and enhanced autocrine secretion of glutamate by cancer cells in response to hydrostatic flow conditions that mimic the high interstitial fluid pressure of the tumor microenvironment. In addition, interstitial flow directly increased NMDAR cell-surface expression and NR2b activation via phosphorylation, resulting in calcium-dependent stimulation of downstream signaling through the mitogen-activated protein kinase (MAPK) and Ca2+/calmodulin-dependent protein kinase (CAMK) pathways. Treatment of pancreatic tumor-bearing mice with NMDAR antagonists attenuated tumor invasion and reduced tumor burden; this antitumor effect was more pronounced in a late-stage regression trial of mice with advanced tumors compared with an early-stage intervention in mice with nascent tumors. These results underscore the importance of mechanotransduction in promoting cancer progression and identify interstitial flow-driven glutamate signaling as a critical regulator of cancer cell invasion. Moreover, these findings support the development of improved glutamate receptor inhibitors for use in patients with NMDAR-expressing tumors.