Galanin modulates the neural niche to favour perineural invasion in head and neck cancer.
Perineural invasion (PNI) is an indicator of poor survival in multiple cancers. Unfortunately, there is no targeted treatment for PNI since the molecular mechanisms are largely unknown. PNI is an active process, suggesting that cancer cells communicate with nerves. However, nerve-tumour crosstalk is understudied due to the lack of in vivo models to investigate the mechanisms. Here we developed an in vivo model of PNI to characterize this interaction. We show that the neuropeptide galanin (GAL) initiates nerve-tumour crosstalk via activation of its G protein-coupled receptor, GALR2. Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2-mediated transcription of cyclooxygenase-2 and GAL. Prostaglandin E2 promotes cancer invasion, and in a feedback mechanism, GAL released by cancer induces neuritogenesis, facilitating PNI. This study describes a novel in vivo model for PNI and reveals the dynamic interaction between nerve and cancer.
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Christina Springstead
CS
Scanlon
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Rajat
R
Banerjee
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Ronald C
RC
Inglehart
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Min
M
Liu
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Nickole
N
Russo
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Amirtha
A
Hariharan
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Elizabeth A
EA
van Tubergen
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Sara L
SL
Corson
1] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Irfan A
IA
Asangani
Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
Charlotte M
CM
Mistretta
1] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Arul M
AM
Chinnaiyan
1] Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Nisha J
NJ
D'Silva
D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018450:Disease Progression; D019004:Galanin / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016501:Neurites / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D044092:Receptor, Galanin, Type 2 / Q000378:metabolism
D050778:NFATC Transcription Factors; D044092:Receptor, Galanin, Type 2; D019004:Galanin; D051546:Cyclooxygenase 2