PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk

Smrita Sinha, Ya Yuan Fu, Adrien Grimont, Maren Ketcham, Kelly Lafaro, Joseph A. Saglimbeni, Gokce Askan, Jennifer M. Bailey, Jerry P. Melchor, Yi Zhong, Min Geol Joo, Olivera Grbovic-Huezo, In Hong Yang, Olca Basturk, Lindsey Baker, Young Park, Robert C. Kurtz, David Tuveson, Steven D. Leach, Pankaj J. Pasricha

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1868-1879
Number of pages12
JournalCancer Research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    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. (2017). PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk. Cancer Research, 77(8), 1868-1879. https://doi.org/10.1158/0008-5472.CAN-16-0899-T