Renz, B. W., Takahashi, R., Tanaka, T., Macchini, M., Hayakawa, Y., Dantes, Z., Maurer, H. C., Chen, X., Jiang, Z., Westphalen, C. B., Ilmer, M., Valenti, G., Mohanta, S. K., Habenicht, A. J. R., Middelhoff, M., Chu, T., Nagar, K., Tailor, Y., Casadei, R., Di Marco, M., Kleespies, A., Friedman, R. A., Remotti, H., Reichert, M., Worthley, D. L., Neumann, J., Werner, J., Iuga, A. C., Olive, K. P., and Wang, T. C. (2018). Cancer Cell 33, 75-90 e77. doi: 10.1016/j.ccell.2017.11.007

Abstract: 

Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain-derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective β-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.