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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, TNF\u03b1 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.<\/jats:p>\n                  <jats:p>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\u201373. \u00a92018 AACR.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 1333<\/jats:p>","DOI":"10.1158\/2159-8290.cd-18-0046","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T10:16:12Z","timestamp":1536142572000},"page":"1458-1473","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":357,"title":["Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness"],"prefix":"10.1158","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-8051","authenticated-orcid":false,"given":"Bernhard W.","family":"Renz","sequence":"first","affiliation":[{"name":"1Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany."},{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."},{"name":"3Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Sunagawa","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Takahashi","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Macchini","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."},{"name":"4Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Dantes","sequence":"additional","affiliation":[{"name":"5Department of Medicine II, Klinikum Rechts der Isar, Technische Universit\u00e4t M\u00fcnchen, Munich, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Valenti","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth A.","family":"White","sequence":"additional","affiliation":[{"name":"6Division of Oncology, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz A.","family":"Middelhoff","sequence":"additional","affiliation":[{"name":"2Division of Digestive and Liver Diseases and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9597-1368","authenticated-orcid":false,"given":"Matthias","family":"Ilmer","sequence":"additional","affiliation":[{"name":"1Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany; 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