title: Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer.
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.
authors.affiliation: Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Jami L
authors.initials: JL
authors.lastname: Saloman
authors.affiliation: Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Albers
authors.affiliation: Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Dongjun
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hartman
authors.affiliation: Department of Internal Medicine, Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261;
authors.forename: Emily A
authors.initials: EA
authors.lastname: Muha
authors.affiliation: Comprehensive Cancer Center and Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109; bmd1@pitt.edu arhim@med.umich.edu.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Rhim
authors.affiliation: Center for Pain Research and Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15261; bmd1@pitt.edu arhim@med.umich.edu.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Davis
mesh_terms: D065311:Adenocarcinoma in Situ / Q000473:pathology / Q000503:physiopathology; D000344:Afferent Pathways; D000818:Animals; D000831:Animals, Newborn; D002211:Capsaicin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy; D002108:Ceruletide / Q000633:toxicity; D003714:Denervation; D018450:Disease Progression; D005260:Female; D005728:Ganglia, Sympathetic / Q000503:physiopathology; D011905:Genes, ras; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009187:Myelitis / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D009361:Neoplasm Invasiveness; D010179:Pancreas / Q000294:innervation*; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control* / Q000628:therapy; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000503:physiopathology; D013133:Spinothalamic Tracts / Q000503:physiopathology; D013904:Thoracic Vertebrae
chemical_list: D002108:Ceruletide; D002211:Capsaicin
keywords: PanIN; inflammation; pancreatic ductal adenocarcinoma; sensory neuron; tumorigenesis