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

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 11; pp. 3078 - 3083
Main Authors:	Saloman, Jami L., Albers, Kathryn M., Li, Dongjun, Hartman, Douglas J., Crawford, Howard C., Muha, Emily A., Rhim, Andrew D., Davis, Brian M.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 15-03-2016 National Acad Sciences
Subjects:	Adenocarcinoma in Situ - pathology Adenocarcinoma in Situ - physiopathology Afferent Pathways Animals Animals, Newborn Biological Sciences Capsaicin - administration & dosage Capsaicin - pharmacology Capsaicin - therapeutic use Carcinoma, Pancreatic Ductal - etiology Carcinoma, Pancreatic Ductal - pathology Carcinoma, Pancreatic Ductal - physiopathology Carcinoma, Pancreatic Ductal - prevention & control Carcinoma, Pancreatic Ductal - therapy Cells Ceruletide - toxicity Denervation Disease Progression Female Ganglia, Sympathetic - physiopathology Genes, ras Humans Male Mice Mice, Inbred C57BL Mice, Transgenic Myelitis - complications Myelitis - genetics Myelitis - physiopathology Neoplasm Invasiveness Nervous system Neurons Pancreas Pancreas - innervation Pancreatic Neoplasms - etiology Pancreatic Neoplasms - pathology Pancreatic Neoplasms - physiopathology Pancreatic Neoplasms - prevention & control Pancreatic Neoplasms - therapy Pancreatitis - chemically induced Pancreatitis - complications Pancreatitis - physiopathology Precancerous Conditions - chemically induced Precancerous Conditions - complications Precancerous Conditions - physiopathology Rodents Sensory Receptor Cells - drug effects Sensory Receptor Cells - physiology Spinal Cord - physiopathology Spinothalamic Tracts - physiopathology Thoracic Vertebrae Tumors sensory neuron tumorigenesis inflammation PanIN pancreatic ductal adenocarcinoma
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Susan G. Amara, National Institutes of Health, Bethesda, MD, and approved February 3, 2016 (received for review June 26, 2015) Author contributions: J.L.S., K.M.A., A.D.R., and B.M.D. designed research; J.L.S., D.L., D.J.H., H.C.C., E.A.M., A.D.R., and B.M.D. performed research; A.D.R. contributed new reagents/analytic tools; J.L.S., K.M.A., D.J.H., A.D.R., and B.M.D. analyzed data; and J.L.S., K.M.A., A.D.R., and B.M.D. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.1512603113