title: Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling.
abstract: Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sakitani
authors.affiliation: Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Department of Medicine, University of Western Ontario, London, ON N6A 5W9, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Niikura
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 5011194, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tomita
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, 81377, Germany.
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Renz
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Macchini
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Moritz
authors.initials: M
authors.lastname: Middelhoff
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Zinaida A
authors.initials: ZA
authors.lastname: Dubeykovskaya
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Woosook
authors.initials: W
authors.lastname: Kim
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Urbanska
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Karan
authors.initials: K
authors.lastname: Nagar
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Department of Internal Medicine III, Klinikum der Universität München, Munich, 81377, Germany.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Department of Internal Medicine II, Klinikum rechts der Isar, II. Technische Universität München, Munich, 81675, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.|Transgenic Mouse Shared Resource, Columbia University, New York, NY, 10032, USA.
authors.forename: Chyuan-Sheng
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gershon
authors.affiliation: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, 5011194, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Trondheim, 7491, Norway.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Zhao
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU - Norwegian University of Science and Technology, Trondheim, 7491, Norway.
authors.forename: Duan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.|Cancer theme, SAHMRI and Department of Medicine, University of Adelaide, SA, 5000, Australia.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Department of Gastroenterology, Graduate school of Medicine, the University of Tokyo, Tokyo, 1138655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, 10032, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D018797:Cell Cycle Proteins; D000089742:Doublecortin-Like Kinases; D005753:Gastric Mucosa / Q000294:innervation; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D043587:Receptor, Muscarinic M3 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013274:Stomach Neoplasms / Q000209:etiology*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D043587:Receptor, Muscarinic M3; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D020932:Nerve Growth Factor; D000089742:Doublecortin-Like Kinases; C485525:Dclk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000109:Acetylcholine
keywords: Dclk1; Lgr5; NGF; YAP; acetylcholine; gastric cancer; muscarinic acetylcholine receptor type 3; stem cell; tuft cell; wnt