American Association for Cancer Research
21598290cd180046-sup-195513_2_supp_4990437_p34g3h.pdf (13.52 MB)

Supplementary Data from Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness

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journal contribution
posted on 2023-04-03, 21:22 authored by Bernhard W. Renz, Takayuki Tanaka, Masaki Sunagawa, Ryota Takahashi, Zhengyu Jiang, Marina Macchini, Zahra Dantes, Giovanni Valenti, Ruth A. White, Moritz A. Middelhoff, Matthias Ilmer, Paul E. Oberstein, Martin K. Angele, Huan Deng, Yoku Hayakawa, C. Benedikt Westphalen, Jens Werner, Helen Remotti, Maximilian Reichert, Yagnesh H. Tailor, Karan Nagar, Richard A. Friedman, Alina C. Iuga, Kenneth P. Olive, Timothy C. Wang

Supplementary Figures, Legends and Methods



Pancreatic Cancer Action Network


Lustgarden Foundation

German Research Foundation

Uehara Memorial Foundation


Mildred-Scheel-Stiftung, Deutsche Krebshilfe

National Science Foundation of China


German Cancer Aid



In many solid tumors, parasympathetic input is provided by the vagus nerve, which has been shown to modulate tumor growth. However, whether cholinergic signaling directly regulates progression of pancreatic ductal adenocarcinoma (PDAC) has not been defined. Here, we found that subdiaphragmatic vagotomy in LSL-Kras+/G12D;Pdx1-Cre (KC) mice accelerated PDAC development, whereas treatment with the systemic muscarinic agonist bethanechol restored the normal KC phenotype, thereby suppressing the accelerated tumorigenesis caused by vagotomy. In LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre mice with established PDAC, bethanechol significantly extended survival. These effects were mediated in part through CHRM1, which inhibited downstream MAPK/EGFR and PI3K/AKT pathways in PDAC cells. Enhanced cholinergic signaling led to a suppression of the cancer stem cell (CSC) compartment, CD11b+ myeloid cells, TNFα levels, and metastatic growth in the liver. Therefore, these data suggest that cholinergic signaling directly and indirectly suppresses growth of PDAC cells, and therapies that stimulate muscarinic receptors may be useful in the treatment of PDAC.Significance: Subdiaphragmatic vagotomy or Chrm1 knockout accelerates pancreatic tumorigenesis, in part via expansion of the CSC compartment. Systemic administration of a muscarinic agonist suppresses tumorigenesis through MAPK and PI3K/AKT signaling, in early stages of tumor growth and in more advanced, metastatic disease. Therefore, CHRM1 may represent a potentially attractive therapeutic target. Cancer Discov; 8(11); 1458–73. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333