PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk Journal Article
| Authors: | Sinha, S.; Fu, Y. Y.; Grimont, A.; Ketcham, M.; Lafaro, K.; 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.; Leach, S. D.; Pasricha, P. J. |
| Article Title: | PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk |
| Abstract: | Nerves are a notable feature of the tumormicroenvironment 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. Nerveresponsive 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. © 2017 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; human cell; nonhuman; cell proliferation; animal cell; mouse; animal tissue; stat3 protein; cell growth; animal experiment; animal model; carcinogenesis; cell culture; cytoplasm; pancreas adenocarcinoma; molecular interaction; nerve cell; innervation; sensory nerve cell; tumor microenvironment; neurokinin 1 receptor; neurosecretory cell; pancreas adenoma; denervation; human; article |
| Journal Title: | Cancer Research |
| Volume: | 77 |
| Issue: | 8 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-04-15 |
| Start Page: | 1868 |
| End Page: | 1879 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-16-0899-t |
| PUBMED: | 28386018 |
| PROVIDER: | scopus |
| PMCID: | PMC5471615 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2017 -- Source: Scopus |
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