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.