Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibres of the sympathetic nervous system (SNS), however the effect of SNS signalling on tumour progression within the pancreatic microenvironment has not previously been investigated. To investigate the effect of neural signalling on cancer progression we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumour cells and their microenvironment. Stress-induced neural activation increased primary tumour growth and tumour cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumour cells and pancreatic stromal cells. Pharmacological activation of beta-adrenergic signalling induced similar effects to chronic stress, and pharmacological beta-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural-induced beta-adrenergic signalling regulates cancer progression within the pancreatic microenvironment and suggest beta-blockade as a novel strategy to complement existing therapies.