An Adrenergic–Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Systemic stress has been shown to promote tumor growth; the sympathetic nervous system–derived stress response molecules catecholamines promote pancreatic ductal adenocarcinoma (PDAC) growth via β-adrenergic signaling. Renz, Takahashi, and colleagues evaluated the effects of systemic catecholamines in the mouse model of Cre-activated mutant Kras pancreatic cancer (KC mice) to interrogate the role of stress in PDAC. Chronic physiologic stress or treatment with the β-adrenergic agonist isoproterenol promoted increased levels of pancreatic intraepithelial neoplastic lesions and neural density in KC mice compared to controls, and KC mouse pancreata and Cre-activated mutant Kras/Trp53^R172H/+ (KPC) mouse pancreatic tumors exhibited increased expression of the β-adrenergic receptor Adrb2 compared to controls. Treatment with the ADRB2 inhibitor ICI 118,551 (ICI) reduced PDAC incidence in chronically stressed KC mice, and combined ICI and gemcitabine treatment reduced tumor growth, decreased adrenergic neuronal density, and increased survival in KPC mice. Neurotrophins, particularly Ngf, were upregulated in KPC EPCAM⁺ cells, and Ngf was upregulated during early KPC PDAC tumorigenesis. In a 3-D culture of KC cells or PDAC cells in vitro, isoproterenol promoted acinar-to-ductal metaplasia and proliferation, and norepinephrine induced NGF upregulation. Isoproterenol promoted axonogenesis, which was ablated by ICI pretreatment. Targeted Ngf overexpression in KPC mice resulted in increased perineural invasion, intratumoral nerve growth, and accelerated tumorigenesis. Pan-TRK inhibitor treatment blocked NGF-dependent growth of murine PDAC cells in vitro, inhibited PDAC growth in KC and KPC mice, and enhanced the antitumor efficacy of gemcitabine in KPC mice. Similarly, ICI treatment enhanced the efficacy of gemcitabine against patient-derived PDAC organoids. Patients with PDAC who had received nonselective β-blockers had significantly better overall survival, decreased nerve density, and lower BDNF levels compared to those who received no β-blockers or β1-selective β-blockers. These findings characterize the stress-induced catecholamine–neurotrophin feedforward loop that promotes PDAC and suggest that targeting this axis may be a potential therapeutic strategy for patients with PDAC.

Renz BW, Takahashi R, Tanaka T, Macchini M, Hayakawa Y, Dantes Z, et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 2017;33:75–90.e7.

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