Sinha, S., Fu, Y. Y., Grimont, A., Ketcham, M., Lafaro, K. J., Saglimbeni, J. A., Askan, G., Bailey, J. M., Melchor, J. P., Zhong, Y., Joo, M. G., Grbovic-Huezo, O., Yang, I. H., Basturk, O., Baker, L., Park, Y., Kurtz, R. C., Tuveson, D. A., Leach, S. D., Pasricha, P. (April 2017) PanIN neuroendocrine cells promote tumorigenesis via neuronal crosstalk. Cancer Res, 77 (8). pp. 1868-1879. ISSN 1538-7445 (Electronic)0008-5472 (Linking)
Abstract
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 crosstalk as a potential novel target in PDAC treatment.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > drugs and therapies > tumor microenvironment |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Signal Transduction CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Tuveson lab CSHL Cancer Center Shared Resources > Animal Shared Resource |
| Depositing User: | Matt Covey |
| Date: | 15 April 2017 |
| Date Deposited: | 25 Jan 2017 21:56 |
| Last Modified: | 07 Jul 2021 14:11 |
| PMCID: | PMC5471615 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34050 |
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