PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk. Academic Article uri icon

Overview

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 cross-talk as a potential novel target in PDAC treatment. Cancer Res; 77(8); 1868-79. ©2017 AACR.

publication date

  • April 6, 2017

Research

keywords

  • Carcinoma, Pancreatic Ductal
  • Neuroendocrine Cells
  • Pancreas
  • Pancreatic Neoplasms
  • Precancerous Conditions
  • Sensory Receptor Cells

Identity

PubMed Central ID

  • PMC5471615

Scopus Document Identifier

  • 85018803901

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-16-0899-T

PubMed ID

  • 28386018

Additional Document Info

volume

  • 77

issue

  • 8