biostudies-literatureHe SNCI NIH HHSE2008-17https://www.ebi.ac.uk/biostudies/studies/S-EPMC4024863biostudies-literatureUnknown111(19)The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and Proceedings of the National Academy of Sciences of the United States of AmericaGFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling.PMC4024863P30 CA008748R01 CA157686R01CA157686T32 CA009685He SBarajas FWong RJChernichenko NBakst RLVakiani EAllen PJChen CHYu ZDeborde SfalseGFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling.The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and 2014-01-01T00:00:00Z2014 May2025-04-05T13:37:34.868Z2019-03-27T01:28:26ZS-EPMC40248632477821310.1073/pnas.1402944111