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However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer, norepinephrine induces ADRB2 (\u03b22-adrenergic receptor)\u2013dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intratumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates colorectal cancer growth through ADRA2A\/Gi-mediated activation of Yes-associated protein (YAP). NGF from CAFs directly enhances colorectal cancer cell growth via the phosphatidylinositol-3-kinase\/AKT pathway. Treatment with a tropomyosin receptor kinase (TRK) inhibitor decreased YAP and AKT activation and colorectal cancer progression in mice. In human colorectal cancer, high NGF expression is associated with mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF\u2013nerve cross-talk in promoting colorectal cancer progression. Blocking this feedforward loop with a TRK inhibitor may represent a potential therapeutic approach for colorectal cancer.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0287","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T12:16:56Z","timestamp":1723551416000},"page":"202-226","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Neuro-Mesenchymal Interaction Mediated by a \u03b22-Adrenergic Nerve Growth Factor Feedforward Loop Promotes Colorectal Cancer Progression"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1717-4870","authenticated-orcid":false,"given":"Hiroki","family":"Kobayashi","sequence":"first","affiliation":[{"name":"1Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center Columbia University Medical Center, New York, New York."},{"name":"2Columbia University 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Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-3097","authenticated-orcid":false,"given":"Ermanno","family":"Malagola","sequence":"additional","affiliation":[{"name":"1Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center Columbia University Medical Center, New York, New York."},{"name":"2Columbia University Digestive and Liver Disease Research Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1367-7638","authenticated-orcid":false,"given":"Xiaofei","family":"Zhi","sequence":"additional","affiliation":[{"name":"1Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center Columbia University Medical Center, New York, New York."},{"name":"2Columbia University Digestive and Liver Disease 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