β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Bernhard W. Renz, Ryota Takahashi, Takayuki Tanaka, Marina Macchini, Yoku Hayakawa, Zahra Dantes, H. Carlo Maurer, Xiaowei Chen, Zhengyu Jiang, C. Benedikt Westphalen, Matthias Ilmer, Giovanni Valenti, Sarajo K. Mohanta, Andreas J.R. Habenicht, Moritz Middelhoff, Timothy Chu, Karan Nagar, Yagnesh Tailor, Riccardo Casadei, Mariacristina Di Marco & 10 others Axel Kleespies, Richard A. Friedman, Helen Remotti, Maximilian Reichert, Daniel L. Worthley, Jens Neumann, Jens Werner, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang

Research output: Contribution to journalArticle

47 Citations (Scopus)

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. Renz et al. show that catecholamines promote ADRB2-dependent pancreatic ductal adenocarcinoma development and secretion of neurotrophins (NT), which in turn promote tumor innervation leading to increased NE and tumor growth. Blockade of ADRB2 or NT receptors improves gemcitabine's therapeutic effect.

LanguageEnglish
Pages75-90.e7
JournalCancer Cell
Volume33
Issue number1
DOIs
Publication statusPublished - 8 Jan 2018

Keywords

  • NGF-BDNF
  • TRK
  • adrenergic signaling
  • neurotrophins
  • pancreatic cancer
  • stress
  • β-blockers

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Renz, B. W., Takahashi, R., Tanaka, T., Macchini, M., Hayakawa, Y., Dantes, Z., ... Wang, T. C. (2018). β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell, 33(1), 75-90.e7. https://doi.org/10.1016/j.ccell.2017.11.007