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; 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

doi:10.1016/j.ccell.2017.11.007

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 MarcoAxel Kleespies, Richard A. Friedman, Helen Remotti, Maximilian Reichert, Daniel L. Worthley, Jens Neumann, Jens Werner, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang

Chair of Urology

Research output: Contribution to journal › Article › peer-review

328 Scopus citations

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.

Original language	English
Pages (from-to)	75-90.e7
Journal	Cancer Cell
Volume	33
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2017.11.007
State	Published - 8 Jan 2018

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2017.11.007

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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., ... 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

@article{0acd1115c2d64d8890d2cae344424497,

title = "β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer",

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.",

keywords = "NGF-BDNF, TRK, adrenergic signaling, neurotrophins, pancreatic cancer, stress, β-blockers",

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

note = "Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2018",

month = jan,

day = "8",

doi = "10.1016/j.ccell.2017.11.007",

language = "English",

volume = "33",

pages = "75--90.e7",

journal = "Cancer Cell",

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publisher = "Cell Press",

number = "1",

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Renz, BW, Takahashi, R, Tanaka, T, Macchini, M, Hayakawa, Y, Dantes, Z, Maurer, HC, Chen, X, Jiang, Z, Westphalen, CB, Ilmer, M, Valenti, G, Mohanta, SK, Habenicht, AJR, Middelhoff, M, Chu, T, Nagar, K, Tailor, Y, Casadei, R, Di Marco, M, Kleespies, A, Friedman, RA, Remotti, H, Reichert, M, Worthley, DL, Neumann, J, Werner, J, Iuga, AC, Olive, KP & Wang, TC 2018, 'β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer', Cancer Cell, vol. 33, no. 1, pp. 75-90.e7. https://doi.org/10.1016/j.ccell.2017.11.007

TY - JOUR

T1 - β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

AU - Renz, Bernhard W.

AU - Takahashi, Ryota

AU - Tanaka, Takayuki

AU - Macchini, Marina

AU - Hayakawa, Yoku

AU - Dantes, Zahra

AU - Maurer, H. Carlo

AU - Chen, Xiaowei

AU - Jiang, Zhengyu

AU - Westphalen, C. Benedikt

AU - Ilmer, Matthias

AU - Valenti, Giovanni

AU - Mohanta, Sarajo K.

AU - Habenicht, Andreas J.R.

AU - Middelhoff, Moritz

AU - Chu, Timothy

AU - Nagar, Karan

AU - Tailor, Yagnesh

AU - Casadei, Riccardo

AU - Di Marco, Mariacristina

AU - Kleespies, Axel

AU - Friedman, Richard A.

AU - Remotti, Helen

AU - Reichert, Maximilian

AU - Worthley, Daniel L.

AU - Neumann, Jens

AU - Werner, Jens

AU - Iuga, Alina C.

AU - Olive, Kenneth P.

AU - Wang, Timothy C.

PY - 2018/1/8

Y1 - 2018/1/8

N2 - 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.

AB - 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.

KW - NGF-BDNF

KW - TRK

KW - adrenergic signaling

KW - neurotrophins

KW - pancreatic cancer

KW - stress

KW - β-blockers

UR - http://www.scopus.com/inward/record.url?scp=85039039634&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2017.11.007

DO - 10.1016/j.ccell.2017.11.007

M3 - Article

C2 - 29249692

AN - SCOPUS:85039039634

SN - 1535-6108

VL - 33

SP - 75-90.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer

Abstract

Keywords

UN SDGs

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