GFRα1 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 cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1(+/-) mice compared with GFRα1(+/+) mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;Department of Otolaryngology, Anhui Provincial Hospital, Anhui Medical University, Anhui 230001, China;
Shuangba
S
He
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Chun-Hao
CH
Chen
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Natalya
N
Chernichenko
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Shizhi
S
He
Department of Radiation Oncology, Mount Sinai Hospital, New York, NY 10029;
Richard L
RL
Bakst
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Fernando
F
Barajas
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Sylvie
S
Deborde
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Peter J
PJ
Allen
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 20021; and.
Efsevia
E
Vakiani
Department of Otolaryngology, Nanjing Tongren Hospital, Southeast University, Nanjing 211102, China.
Zhenkun
Z
Yu
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; wongr@mskcc.org.
Richard J
RJ
Wong
D016475:3T3 Cells; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009417:Nerve Tissue / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D020426:Sciatic Neuropathy / Q000378:metabolism / Q000473:pathology; D012995:Solubility
C494987:GFRA1 protein, human; C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human