Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

Jami L. Saloman, Kathryn M. Albers, Dongjun Li, Douglas J. Hartman, Howard C. Crawford, Emily A. Muha, Andrew D. Rhim, Brian M. Davis

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.

Original languageEnglish (US)
Pages (from-to)3078-3083
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number11
DOIs
StatePublished - Mar 15 2016

Keywords

  • Inflammation
  • PanIN
  • Pancreatic ductal adenocarcinoma
  • Sensory neuron
  • Tumorigenesis

ASJC Scopus subject areas

  • General

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