RT Journal Article SR Electronic T1 PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk JF Cancer Research JO Cancer Res FD American Association for Cancer Research SP 1868 OP 1879 DO 10.1158/0008-5472.CAN-16-0899 VO 77 IS 8 A1 Sinha, Smrita A1 Fu, Ya-Yuan A1 Grimont, Adrien A1 Ketcham, Maren A1 Lafaro, Kelly A1 Saglimbeni, Joseph A. A1 Askan, Gokce A1 Bailey, Jennifer M. A1 Melchor, Jerry P. A1 Zhong, Yi A1 Joo, Min Geol A1 Grbovic-Huezo, Olivera A1 Yang, In-Hong A1 Basturk, Olca A1 Baker, Lindsey A1 Park, Young A1 Kurtz, Robert C. A1 Tuveson, David A1 Leach, Steven D. A1 Pasricha, Pankaj J. YR 2017 UL http://cancerres.aacrjournals.org/content/77/8/1868.abstract AB Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here, we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and STAT3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of STAT3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial cross-talk as a potential novel target in PDAC treatment. Cancer Res; 77(8); 1868–79. ©2017 AACR.